WO2001051469A1 - Piperidine and piperazine derivatives which function as 5-ht2a receptor antagonists - Google Patents

Piperidine and piperazine derivatives which function as 5-ht2a receptor antagonists Download PDF

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Publication number
WO2001051469A1
WO2001051469A1 PCT/EP2001/000080 EP0100080W WO0151469A1 WO 2001051469 A1 WO2001051469 A1 WO 2001051469A1 EP 0100080 W EP0100080 W EP 0100080W WO 0151469 A1 WO0151469 A1 WO 0151469A1
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Prior art keywords
ethyl
fluorophenyl
hydrochloride
piperidine
formula
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PCT/EP2001/000080
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German (de)
French (fr)
Inventor
Karl-August Ackermann
Henning Böttcher
Helmut Prücher
Christoph Van Amsterdam
Christoph Seyfried
Hartmut Greiner
Gerd Bartoszyk
Jürgen Harting
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Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to AU2001233685A priority Critical patent/AU2001233685A1/en
Priority to JP2001551851A priority patent/JP2004500373A/en
Priority to HU0300052A priority patent/HUP0300052A3/en
Priority to EP01905650A priority patent/EP1246803A1/en
Priority to CA002396007A priority patent/CA2396007A1/en
Priority to BR0107578-0A priority patent/BR0107578A/en
Priority to SK971-2002A priority patent/SK9712002A3/en
Priority to KR1020027008493A priority patent/KR20020073492A/en
Priority to MXPA02006809A priority patent/MXPA02006809A/en
Publication of WO2001051469A1 publication Critical patent/WO2001051469A1/en
Priority to NO20023293A priority patent/NO20023293L/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds of the formula
  • R 1 , R 2 are each independently an unsubstituted or substituted by R 3 , R 4 and / or R 5 or
  • Naphthyl or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, OH, CN, N0 2 , NH 2 ,
  • NHA NHA, NA 2 , NH-acyl, acyl, -SA, -SOA, S0 2 A, COOA or
  • alkyi with 1 -6 C atoms
  • alk alkylene with 1-6 C atoms
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their physiologically acceptable salts and solvates have valuable pharmacological properties with good tolerability, since they have effects on the central nervous system. The connections are strong
  • test can be used, for example, for in-vitro detection of the affinity for 5-HT ⁇ receptors.
  • the 5-HT 2A receptors are exposed to both [ 3 H] ketanserin (a substance known for its affinity for the receptor) and the test compound.
  • the decrease in the affinity of [ 3 H] ketanserin for the receptor is an indication of the affinity of the test substance for the 5-HT2A receptor.
  • the detection is carried out analogously to the description by JE Leysen et al., Molecular
  • the activity of the compounds according to the invention as 5-HT 2A receptor antagonists can be determined in vitro analogously to W. Feniuk et al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction, in: The Peripheral Actions of 5-Hydroxytryptamine, ed. Fozard JR, Oxford University Press, New York, 1989, p.1 10.
  • the contractility of the rat tail artery, caused by 5-hydroxytryptamine is mediated by 5-HT 2A receptors.
  • vascular rings prepared from the ventral rat tail artery, are perfused in an organ bath with an oxygen-saturated solution.
  • a response to the cumulative concentration of 5-HT is obtained by adding increasing concentrations of 5-hydroxytryptamine to the solution.
  • the test compound is then added to the organ bath in suitable concentrations and a second concentration curve for 5-HT is measured.
  • the strength of the test compound on the shift of the 5-HT-induced concentration curve to higher 5-HT concentrations is a measure of the 5-HT 2A receptor anatgonistic property in vitro.
  • the 5-HTz ⁇ -antagonistic property can be determined in vivo analogously to MDSerdar et al., Psychopharmacoiogy, 1996, 128: 198-205.
  • the compounds of the formula I are suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and of inflammation. They can be used for prophylaxis and to combat the consequences of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia, as well as for
  • Alzheimer's disease sleep disorders, tardive dyskinesia, Leming disorders, age-related memory disorders, eating disorders such as bulimia, drug abuse and / or sexual dysfunction. Furthermore, they are suitable for the treatment of endocrine diseases such as hyperprolactinaemia, also for vasospasm, hypertension and gastrointestinal diseases.
  • endocrine diseases such as hyperprolactinaemia, also for vasospasm, hypertension and gastrointestinal diseases.
  • the compounds according to the invention can also be used together with other active ingredients in the treatment of schizophrenia.
  • Other compounds which may be used are the compounds mentioned in WO 99/11641 on page 13, lines 20-26.
  • the invention relates to the piperidine and piperazine derivatives of the formula I and their physiologically acceptable acid addition salts.
  • the invention also relates to the solvates, e.g. Hydrates or alcoholates, of these compounds.
  • the invention accordingly relates to the compounds of the formula I and processes for the preparation of compounds of the formula I according to claim 1.
  • radicals R 1 and / or R 2 optionally converting one of the radicals R 1 and / or R 2 into another radical R 1 and / or R 2 , for example by cleaving an OA group to form an OH group and / or a CHO group into a CN Group converts
  • Claim 1 wherein X is CH, is characterized in that
  • R 2 has the meaning given in claim 1, with a compound of formula V.
  • radicals R 1 and / or R 2 optionally converting one of the radicals R 1 and / or R 2 into another radical R 1 and / or R 2 , for example by cleaving an OA group to form an OH group and / or a CHO group into a CN Group converts
  • the invention also relates to the compounds of the formula I as claimed in claim 1, and to their physiologically acceptable salts and solvates as medicaments.
  • the invention relates in particular to the compounds of the formula I. wherein
  • R 1 , R 2 are each independently an unsubstituted or substituted by R 3 , R 4 and / or R 5 or
  • Naphthyl or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, OH, CN, N0 2 , NH 2 ,
  • NHA NHA, NA 2 , NH-acyl, acyl, -SA, -SOA, S0 2 A, COOA or
  • alkyl with 1-6 C atoms alk alkylene with 1-6 C atoms
  • the present invention also provides the compounds of formula I and their enantiomers and diastereomers and salts thereof.
  • the radical A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4, in particular 1 or 2, carbon atoms.
  • Alkyl therefore means in particular, for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1 , 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-,
  • Acyl preferably has 1-6 C atoms and means e.g. Formyl, acetyl, propionyl, butyryl, also trifluoroacetyl.
  • Alkylene has 1, 2, 3, 4, 5 or 6 carbon atoms, is unbranched or branched and preferably means methylene, ethylene, propylene, or butylene
  • Alkylene very particularly preferably means ethylene.
  • OA is preferably methoxy, trifluoromethoxy, and also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
  • R 1 and R 2 each independently represent unsubstituted, preferably - as indicated - substituted by R 3 and / or R 4 substituted phenyl or naphthyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-
  • R 1 and R 2 are each independently Het 1 .
  • Het 1 is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or
  • 5-oxazolyl 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-thazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4-thiadiazol-2- or -5 -yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-
  • R 1 very particularly preferably denotes phenyl, p-chlorophenyl, p-fluorophenyl, thiophene-2-yl, 5-chloro-thiophene-2-yl, 2,5-dichloro-thiophene-3-yl and 2- or 3-furyl ,
  • R 2 very particularly preferably denotes 4-propylphenyl, 2-isopropylphenyl, butyl, 2,4,6-trimethylphenyl, 2- or 4-methoxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylphenyl , 2- or 4-chlorophenyl, 2-nitrophenyl, 4'-biphenyl, 2,4,6-trimethylphenyl, 3,4-
  • the invention also relates to the compounds 4- ⁇ 4- [2- (4-
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ik, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which in la R denotes a phenyl or naphthyl radical or Het 1 substituted by R 3 , R 4 and / or R 5 ; in Ib R 1 denotes a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 ; in Ic R 1 a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 ,
  • R 2 represents a phenyl or naphthyl radical or Het 1 substituted by R 3 , R 4 and / or R 5 ; in Id R 1 is a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 , R 2 is a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 or Het 1 , Het 1 is unsubstituted or a - or twice by shark, CN,
  • R 2 is a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 or Het 1 , Het 1 unsubstituted or mono- or disubstituted by shark, CN,
  • R 1 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical
  • R 2 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical or Het 1 ,
  • R 3 , R 4 , R 5 each independently of one another shark, CN, -SA, A,
  • R 1 is substituted by R 3 , R 4 and / or R 5
  • Phenyl radical, R 2 is a substituted by R 3 , R 4 and / or R 5
  • R 3 , R 4 , R 5 each independently of one another shark, CN, -SA, A,
  • R 1 is a phenyl or naphthyl radical which is unsubstituted or substituted by R 3 , R 4 and / or R 5
  • R 2 is an unsubstituted or substituted by R 3 , R 4 and / or R 5 phenyl or naphthyl radical or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, NH 2 , NHA, ⁇ * NA 2 , NH-acyl, acyl or phenyl,
  • R 1 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical
  • R 2 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, NH 2 , NHA,
  • NA 2 NH-acyl, acyl or phenyl, Het 1 unsubstituted or mono- or disubstituted by shark, CN,
  • R 1 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical
  • R 2 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical 33 or Het 1
  • R 3 , R 4 , R 5 are each independently of one another shark, A, OA, NH 2 , NHA, NA 2 , NH-acyl, acyl or phenyl,
  • R 1 is an unsubstituted or substituted by R 3 , R 4 and / or R 5 ,
  • R 2 is a phenyl radical which is unsubstituted or substituted by R 3 , R 4 and / or R 5
  • R 3 , R 4 , R 5 each independently represent shark, A, COOA or OA, alk alkylene with 1-4 C atoms;
  • Het 1 ⁇ 2,1, 3-benzoxadiazol- or 2,1, 3-benzothiadiazol-yl, and their physiologically acceptable salts and solvates.
  • Manufacture is otherwise produced according to methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; ) are described, namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
  • the starting materials for the claimed process can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately passed on to the compounds of Formula I implements. On the other hand, it is possible to carry out the reaction in stages.
  • the radical L is preferably Cl or Br; however, it can also mean 1, OH or, preferably, a reactive, functionally modified OH group, in particular alkylsulfonyloxy with 1-6 (e.g. methanesulfonyloxy) or aryisulfonyloxy with 6-10 C atoms (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2 - Naphthalenesulfonyloxy) or trichloromethoxy, alkoxy, such as Methoxy, ethoxy, propoxy or butoxy, also phenoxy.
  • alkylsulfonyloxy with 1-6 e.g. methanesulfonyloxy
  • aryisulfonyloxy with 6-10 C atoms e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2 -
  • the compounds of the formula I in which X is N can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
  • the starting materials of formulas II and III are generally known; the unknown compounds of formulas II and III can easily be prepared analogously to the known compounds.
  • reaction of the compounds II and III proceeds according to methods known from the literature for the alkylation or acylation of amines. However, it is also possible to react the compounds in the presence of an inert solvent. Suitable solvents are e.g. Hydrocarbons such as benzene, toluene, xylene; Ketones such as acetone, butanone; Alcohols such as methanol, ethanol, isopropanol, N-butanol;
  • Ethers such as tetrahydrofuran (THF) or dioxane; Amides such as dimethylformamide (DMF) or N-methylpyrrolidone; Nitriles such as acetonitrile, optionally also mixtures of these solvents with one another or mixtures with water.
  • an acid-binding agent for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylaniiine, Pyridine or quinoline or an excess of piperazine derivative of formula II may be beneficial.
  • the reaction time is between a few minutes and 14 days. tion temperature between about 0 and 150 °, usually between 20 and 130 °.
  • compounds of the formula I in which X is CH can be prepared by reacting amines of the formula IV with a component of the formula V and then oxidizing the reaction product.
  • the oxidation generally produces a mixture of sulfinyl and sulfonyl compounds, which can be separated into the individual compounds by chromatography or by crystallization.
  • the respective components are generally known or, as already described, can be produced by known processes.
  • the reaction between the compounds of the formula IV and V proceeds under conditions as described for the reaction between the compounds of the formula II and III.
  • a base of the formula I obtained can be converted into the associated acid addition salt using an acid.
  • Acids which provide physiologically acceptable salts are suitable for this reaction.
  • Inorganic acids can be used, e.g. Sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, acetic acid
  • the free bases of the formula I can be obtained from their salts by treatment with strong bases such as sodium or potassium hydroxide,
  • bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary
  • the invention furthermore relates to the medicaments according to the invention with 5-HT 2A receptor antagonistic activity for the treatment of psychoses, schizophrenia, depression, neurological disorders,
  • the invention also relates to a pharmaceutical preparation containing at least one medicament according to the invention and, if appropriate, carriers and / or auxiliaries and, if appropriate, other active compounds.
  • the medicinal products can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention furthermore relates to the use of the compounds according to the invention and / or of their physiologically acceptable salts and solvates for the production of a medicament with 5-HT 2A - receptor-antagonistic activity.
  • the invention also relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament with 5-HTz ⁇ - receptor-antagonistic activity for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease , amyotrophic lateral sclerosis, Alzheimer's Disease, Huntington's disease, eating disorders such as bulimia, nervous anorexia, premenstrual syndrome and / or to positively influence compulsive behavior (obsessive-compulsive disorder, OCD).
  • psychoses schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease , amyotrophic lateral sclerosis, Alzheimer's Disease, Huntington's disease, eating disorders such as bulimia, nervous anorexia, premenstrual syndrome and / or to positively influence compulsive behavior (obsessive-compulsive disorder, OCD).
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohol, polyethylene glycols, gelatin, carbohydrates such as lactose or starch , Magnesium stearate, talc, petroleum jelly. Tablets, coated tablets, capsules, syrups, juices, drops or suppositories are used in particular for enteral administration, solutions, preferably oily or aqueous solutions, and further suspensions are used for parenteral administration.
  • Emulsions or implants for topical application of ointments, creams or powders.
  • the new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins.
  • the substances according to the invention are generally administered in analogy to known preparations, preferably in doses between about 0.1 and 500 mg, in particular between 5 and 300 mg per dosage unit.
  • the daily dosage is preferably between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg body weight.
  • the substances according to the invention are generally preferably used in doses between about 1 and 500 mg, in particular administered between 5 and 100 mg per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each particular patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion, Drug combination and severity of the disease to which the therapy applies. Oral application is preferred.
  • customary work-up means: if necessary, the solvent is removed, water is added if necessary and, if necessary, the pH is adjusted to between 2 and 10, depending on the constitution of the end product, extracted with ethyl acetate or dichloromethane, separates, the organic phase dries over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel and / or by crystallization.
  • Frontal rat cortex is homogenized in ice-cold buffer.
  • Homogenate is centrifuged at 4 ° C and 50000 X for 10 minutes. The pellet is resuspended in 2.5 ml ice-cold Tris buffer, with an additional 10 ml
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of Na 2 HP0 4 x 2 H 2 0, 28.48 g of NaH 2 P0 4 x 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is filled into ampoules, lyophilized under aseptic conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

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Abstract

The invention relates to compounds of formula (I), wherein R1, R2, X, Y and alk are defined as per claim 1, are potent 5-HT¿2A? antagonists and are suitable for treating psychosis, schizophrenia, depression, neurological disorders, impaired memory, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders, such as bulimia and anorexia nervosa, premenstrual syndrome and/or for positively influencing compulsive behaviour (obsessive-compulsive disorder, OCD).

Description

PIPERIDIN- UND PIPERAZINDERIVATE ALS 5-HT2A REZEPTOR ANTAGONISTENPIPERIDINE AND PIPERAZINE DERIVATIVES AS 5-HT2A RECEPTOR ANTAGONISTS
Die Erfindung betrifft Verbindungen der FormelThe invention relates to compounds of the formula
Figure imgf000002_0001
worin
Figure imgf000002_0001
wherein
R1, R2 jeweils unabhängig voneinander einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oderR 1 , R 2 are each independently an unsubstituted or substituted by R 3 , R 4 and / or R 5 or
Naphthylrest oder Het1, R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, OH, CN, N02, NH2,Naphthyl or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, OH, CN, N0 2 , NH 2 ,
NHA, NA2, NH-Acyl, Acyl, -SA, -SOA, S02A, COOA oderNHA, NA 2 , NH-acyl, acyl, -SA, -SOA, S0 2 A, COOA or
Phenyl, X CH oder N,Phenyl, X CH or N,
Y S02 wenn X = N, oderY S0 2 if X = N, or
S, SO, S02 wenn X = CH, Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, A, CN,S, SO, S0 2 if X = CH, Het 1 unsubstituted or one, two or three times by shark, A, CN,
CONH2, CH2COOA, Phenyl-S02, Acyl, OA oder OH substituiertes ungesättigtes heterocyclisches Ringsystem, welches eines, zwei oder drei gleiche oder verschiedene Heteroatome wie Stickstoff, Sauerstoff und Schwefel enthält,CONH 2 , CH 2 COOA, phenyl-S0 2 , acyl, OA or OH substituted unsaturated heterocyclic ring system which contains one, two or three identical or different heteroatoms such as nitrogen, oxygen and sulfur,
A Alkyi mit 1 -6 C-Atomen, alk Alkylen mit 1-6 C-Atomen,A alkyi with 1 -6 C atoms, alk alkylene with 1-6 C atoms,
Hai F, Cl, Br oder I, bedeuten, wobei Het1 ≠2,1 ,3-Benzoxadiazol- oder 2,1 , 3-Benzothiadiazol-yl, sowie deren physiologisch unbedenklichen Salze und Solvate.Shark F, Cl, Br or I, where Het 1 ≠ 2,1, 3-benzoxadiazol- or 2,1, 3-benzothiadiazol-yl, and their physiologically acceptable salts and solvates.
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können. Es wurde gefunden, dass die Verbindungen der Formel I und ihre physiologisch unbedenklichen Salze und Solvate bei guter Verträglichkeit wertvolle pharmakologische Eigenschaften besitzen, da sie Wirkungen auf das Zentralnervensystem besitzen. Die Verbindungen weisen eine starkeThe invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments. It has been found that the compounds of the formula I and their physiologically acceptable salts and solvates have valuable pharmacological properties with good tolerability, since they have effects on the central nervous system. The connections are strong
Affinität zu 5-HT^-Rezeptoren auf, weiterhin zeigen sie 5-HT^-Rezeptor- antagonistische Eigenschaften.Affinity to 5-HT ^ receptors, they also show 5-HT ^ receptor antagonistic properties.
Zum in-vitro Nachweis der Affinität zu 5-HT^-Rezeptoren kann beispiels- weise folgender Test (Beispiel A1 ) herangezogen werden. Die 5-HT2A Rezeptoren werden sowohl [3H]Ketanserin (eine Substanz, bekannt für ihre Affinität zum Rezeptor) als auch der Testverbindung ausgesetzt. Die Abnahme der Affinität von [3H]Ketanserin zum Rezeptor ist ein Anzeichen für die Affinität der Testsubstanz zum 5-HT2A Rezeptor. Der Nachweis erfolgt analog der Beschreibung von J.E. Leysen et al., MolecularThe following test (example A1) can be used, for example, for in-vitro detection of the affinity for 5-HT ^ receptors. The 5-HT 2A receptors are exposed to both [ 3 H] ketanserin (a substance known for its affinity for the receptor) and the test compound. The decrease in the affinity of [ 3 H] ketanserin for the receptor is an indication of the affinity of the test substance for the 5-HT2A receptor. The detection is carried out analogously to the description by JE Leysen et al., Molecular
Pharmacology, 1982, 21 : 301-314 oder wie z.B. auch in EP 0320983 beschrieben.Pharmacology, 1982, 21: 301-314 or as e.g. also described in EP 0320983.
Die Wirksamkeit der erfindungsgemäßen Verbindungen als 5-HT2A Rezeptor-Antagonisten kann in vitro analog W. Feniuk et al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction, in: The Peripheral Actions of 5-Hydroxytryptamine, ed. Fozard JR, Oxford University Press, New York, 1989, p.1 10, gemessen werden. So wird die Kontraktilität der Rattenschwanzarterie, hervorgerufen durch 5-Hydroxytryptamin, durch 5- HT2A Rezeptoren vermittelt. Für das Testsystem werden Gefäßringe, präpariert aus der ventralen Rattenschwanzarterie, in einem Organbad mit einer sauerstoffgesättigten Lösung einer Perfusion unterzogen. Durch Eintrag ansteigender Konzentrationen an 5-Hydroxytryptamin in die Lösung erhält man eine Antwort auf die kumulative Konzentration an 5-HT. Danach wird die Testverbindung in geeigneten Konzentrationen in das Organbad gegeben und eine zweite Konzentrationskureve für 5-HT gemessen. Die Stärke der Testverbindung auf die Verschiebung der 5-HT induzierten Konzentrationskurve zu höheren 5-HT Konzentrationen ist ein Maß für die 5-HT2A-Rezeptor-anatgonistische Eigenschaft in vitro. Die 5-HTz^-antagonistische Eigenschaft kann in vivo analog M.D.Serdar et al., Psychopharmacoiogy, 1996, 128: 198-205, bestimmt werden.The activity of the compounds according to the invention as 5-HT 2A receptor antagonists can be determined in vitro analogously to W. Feniuk et al., Mechanisms of 5-hydroxytryptamine-induced vasoconstriction, in: The Peripheral Actions of 5-Hydroxytryptamine, ed. Fozard JR, Oxford University Press, New York, 1989, p.1 10. The contractility of the rat tail artery, caused by 5-hydroxytryptamine, is mediated by 5-HT 2A receptors. For the test system, vascular rings, prepared from the ventral rat tail artery, are perfused in an organ bath with an oxygen-saturated solution. A response to the cumulative concentration of 5-HT is obtained by adding increasing concentrations of 5-hydroxytryptamine to the solution. The test compound is then added to the organ bath in suitable concentrations and a second concentration curve for 5-HT is measured. The strength of the test compound on the shift of the 5-HT-induced concentration curve to higher 5-HT concentrations is a measure of the 5-HT 2A receptor anatgonistic property in vitro. The 5-HTz ^ -antagonistic property can be determined in vivo analogously to MDSerdar et al., Psychopharmacoiogy, 1996, 128: 198-205.
Andere Verbindungen, die ebenfalls 5-HT2-antagonistische Wirkungen zeigen, sind beispielweise in der EP 0320983 beschrieben.Other compounds which also show 5-HT 2 -antagonistic effects are described for example in EP 0320983.
Anders substituierte Piperazinderivate mit antiarrhythmischen Eigenschaften sind z.B. in der EP 0431944 und EP 0431945 offenbart. Andere Indol- carbonylderivate mit analgetischen Eigenschaften sind in der EP 0599240 beschrieben. In der EP 0624584 sind Piperazinderivate als Caimodolin- Inhibitoren beschrieben. In der WO 99/11641 sind Phenylindoiderivate mitOther substituted piperazine derivatives with antiarrhythmic properties are e.g. disclosed in EP 0431944 and EP 0431945. Other indole carbonyl derivatives with analgesic properties are described in EP 0599240. EP 0624584 describes piperazine derivatives as caimodoline inhibitors. WO 99/11641 includes phenylindoid derivatives
5-HT2-antagonistischen Eigenschaften beschrieben. Anders substituierte 4-(Phenylsulfonyl)-pipehdinderivate als Wirkstoffe gegen Arrythmien sind in der EP 304888 beschrieben. A. Morikawa et al. beschreiben in Chem. Pharm. Bull. (1992), 40, 770-3, 5- Isochinolinsulfonamide als Vasodilatatoren.5-HT 2 antagonistic properties described. Differently substituted 4- (phenylsulfonyl) pipehinder derivatives as active ingredients against arrhythmias are described in EP 304888. A. Morikawa et al. describe in Chem. Pharm. Bull. (1992), 40, 770-3, 5-isoquinoline sulfonamides as vasodilators.
H. Hidaka et al. offenbaren andere 5-lsochinolinsulfonamide alsH. Hidaka et al. disclose 5-isoquinoline sulfonamides other than
Vasodilatatoren in EP 61673.Vasodilators in EP 61673.
M.Ohashi et al. beschreiben in JP 63176177 Piperazinsulfonylderivate alsM.Ohashi et al. describe in JP 63176177 piperazinesulfonyl derivatives as
Entfärbemittel.Dye removers.
Die Verbindungen der Formel I eignen sich sowohl in der Veterinär- als auch in der Humanmedizin zur Behandlung von Funktionsstörungen des Zentralnervensystems sowie von Entzündungen. Sie können zur Prophylaxe und zur Bekämpfung der Folgen cerebraler Infarktgeschehen (apoplexia cerebri) wie Schlaganfall und cerebraler Ischämien sowie zurThe compounds of the formula I are suitable both in veterinary and in human medicine for the treatment of functional disorders of the central nervous system and of inflammation. They can be used for prophylaxis and to combat the consequences of cerebral infarction (apoplexia cerebri) such as stroke and cerebral ischemia, as well as for
Behandlung extrapyramidal-motorischer Nebenwirkungen von Neurolep- tika sowie des Morbus Parkinson, zur akuten und symptomatischen Therapie der Alzheimer Krankheit sowie zur Behandlung der amyotrophen Lateralsklerose verwendet werden. Ebenso eignen sie sich als Therapeu- tika zur Behandlung von Hirn- und Rückenmarkstraumata. Insbesondere sind sie jedoch geeignet als Arzneimittelwirkstoffe für Anxiolytika, Antide- pressiva, Antipsychotika, Neuroleptika, Antihypertonika und/oder zur positiven Beeinflussung von Zwangsverhalten (obsessive-compulsive disorder, OCD), Angstzuständen, Panikattacken, Psychosen, Schizophrenie, Anorexie, wahnhaften Zwangsvorstellungen, Agoraphobie, Migräne, derTreatment of extrapyramidal motor side effects of neuroleptics and Parkinson's disease, for the acute and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. They are also suitable as therapeutic agents for the treatment of brain and spinal cord trauma. In particular, however, they are suitable as active pharmaceutical ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensives and / or for positively influencing obsessive-compulsive behavior (obsessive-compulsive disorder, OCD), anxiety, panic attacks, psychoses, schizophrenia, anorexia, delusional obsession , Migraine, the
Alzheimer Krankheit, Schlafstörungen, tardiver Dyskinesien, Lemstörungen, altersabhängiger Erinnerungsstörungen, Essstörungen wie Bulimie, Drogenmissbrauch und/oder Sexualfunktionsstörungen. Desweiteren sind sie geeignet zur Behandlung von endokrinen Erkrankungen wie Hyperprolactinaemie, ferner bei Vasospasmen, Hypertension und gastrointestinalen Erkrankungen.Alzheimer's disease, sleep disorders, tardive dyskinesia, Leming disorders, age-related memory disorders, eating disorders such as bulimia, drug abuse and / or sexual dysfunction. Furthermore, they are suitable for the treatment of endocrine diseases such as hyperprolactinaemia, also for vasospasm, hypertension and gastrointestinal diseases.
Ferner sind sie geeignet zur Behandlung cardiovaskulärer Erkrankungen sowie extrapyramidaler Symptome wie in der WO 99/11641 auf Seite 2, Zeile 24-30 beschrieben. Die erfindungsgemäßen Verbindungen eignen sich weiter zurThey are also suitable for the treatment of cardiovascular diseases and extrapyramidal symptoms, as described in WO 99/11641 on page 2, lines 24-30. The compounds of the invention are also suitable for
Verminderung des Augeninnendruckes und zur Glaucombehandlung. Sie sind auch zur Prophylaxe und Behandlung von Vergiftungserscheinungen bei der Gabe von Ergovalin bei Tieren geeignet. Die Verbindungen eignen sich weiterhin zur Behandlung von Erkran- kungen des Herz-Kreislaufsystems (WO 99/11641 , Seite 3, Zeile 14-15).Reduction of intraocular pressure and for glaucoma treatment. They are also suitable for the prophylaxis and treatment of poisoning symptoms when ergovalin is administered to animals. The compounds are furthermore suitable for the treatment of diseases of the cardiovascular system (WO 99/11641, page 3, lines 14-15).
Die erfindungsgemäßen Verbindungen können auch zusammen mit anderen Wirkstoffen in der Behandlung der Schizophrenie eingesetzt werden. Als andere Wirkstoffe kommen die in der WO 99/11641 auf Seite 13, Zeile 20-26 genannten Verbindungen in Frage.The compounds according to the invention can also be used together with other active ingredients in the treatment of schizophrenia. Other compounds which may be used are the compounds mentioned in WO 99/11641 on page 13, lines 20-26.
Ferner können sie als Zwischenprodukte zur Herstellung weiterer Arzneimittelwirkstoffe eingesetzt werden.They can also be used as intermediates for the production of further active pharmaceutical ingredients.
Gegenstand der Erfindung sind die Piperidin- und Piperazinderivate der Formel I sowie ihre physiologisch unbedenklichen Säureadditionssalze.The invention relates to the piperidine and piperazine derivatives of the formula I and their physiologically acceptable acid addition salts.
Gegenstand der Erfindung sind auch die Solvate, z.B. Hydrate oder Alkoholate, dieser Verbindungen.The invention also relates to the solvates, e.g. Hydrates or alcoholates, of these compounds.
Gegenstand der Erfindung sind dementsprechend die Verbindungen der Formel I sowie Verfahren zur Herstellung von Verbindungen der Formel I gemäß Anspruch 1.The invention accordingly relates to the compounds of the formula I and processes for the preparation of compounds of the formula I according to claim 1.
Das Verfahren zur Herstellung von Verbindungen der Formel I gemäß Anspruch 1 , worin X N bedeutet, ist dadurch gekennzeichnet, daß man a) eine Verbindung der Formel IIThe process for the preparation of compounds of the formula I according to claim 1, in which X is N, is characterized in that a) a compound of formula II
Figure imgf000006_0001
Figure imgf000006_0001
worin R1 und alk die in Anspruch 1 angegebenen Bedeutungen haben, mit einer Verbindung der Formel IIIwherein R 1 and alk have the meanings given in claim 1, with a compound of formula III
R -Y-LR -Y-L
worin L Cl, Br, I oder eine freie oder reaktionsfähig funktioneil abgewandelte OH-Gruppe bedeutet, und R2 und Y die in Anspruch 1 angegebenen Bedeutungen haben,in which L is Cl, Br, I or a free or reactive functional OH group, and R 2 and Y have the meanings given in Claim 1,
umsetzt,implements,
oderor
b) gegebenenfalls einen der Reste R1 und/oder R2 in einen anderen Rest R1 und/oder R2 umwandelt, indem man beispielsweise eine OA-Gruppe unter Bildung einer OH-Gruppe spaltet und/oder eine CHO-Gruppe in eine CN-Gruppe umwandeltb) optionally converting one of the radicals R 1 and / or R 2 into another radical R 1 and / or R 2 , for example by cleaving an OA group to form an OH group and / or a CHO group into a CN Group converts
und/oder eine erhaltene Base der Formel I durch Behandeln mit einer Säure in eines ihrer Salze umwandelt.and / or converts a base of the formula I obtained into one of its salts by treatment with an acid.
Das Verfahren zur Herstellung von Verbindungen der Formel I gemäßThe process for the preparation of compounds of formula I according to
Anspruch 1 , worin X CH bedeutet, ist dadurch gekennzeichnet, daß manClaim 1, wherein X is CH, is characterized in that
a) eine Verbindung der Formel IV
Figure imgf000007_0001
a) a compound of formula IV
Figure imgf000007_0001
worin R2 die in Anspruch 1 angegebene Bedeutung hat, mit einer Verbindung der Formel Vwherein R 2 has the meaning given in claim 1, with a compound of formula V.
R1-alk-L VR 1 -alk-L V
worin L Cl, Br, I oder eine freie oder reaktionsfähig funktionell abgewandelte OH-Gruppe bedeutet, und R1 und alk die in Anspruch 1 angegebenen Bedeutungen haben,in which L is Cl, Br, I or a free or reactively functionally modified OH group, and R 1 and alk have the meanings given in Claim 1,
umsetzt,implements,
und anschließend oxidiert,and then oxidized,
oderor
b) gegebenenfalls einen der Reste R1 und/oder R2 in einen anderen Rest R1 und/oder R2 umwandelt, indem man beispielsweise eine OA-Gruppe unter Bildung einer OH-Gruppe spaltet und/oder eine CHO-Gruppe in eine CN-Gruppe umwandeltb) optionally converting one of the radicals R 1 and / or R 2 into another radical R 1 and / or R 2 , for example by cleaving an OA group to form an OH group and / or a CHO group into a CN Group converts
und/oder eine erhaltene Base der Formel I durch Behandeln mit einer Säure in eines ihrer Salze umwandelt.and / or converts a base of the formula I obtained into one of its salts by treatment with an acid.
Gegenstand der Erfindung sind auch die Verbindungen der Formel I gemäß Anspruch 1 , sowie ihrer physiologisch unbedenklichen Salze und Solvate als Arzneimittel.The invention also relates to the compounds of the formula I as claimed in claim 1, and to their physiologically acceptable salts and solvates as medicaments.
Gegenstand der Erfindung sind insbesondere die Verbindungen der Formel I
Figure imgf000008_0001
worinThe invention relates in particular to the compounds of the formula I.
Figure imgf000008_0001
wherein
R1, R2 jeweils unabhängig voneinander einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oderR 1 , R 2 are each independently an unsubstituted or substituted by R 3 , R 4 and / or R 5 or
Naphthylrest oder Het1, R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, OH, CN, N02, NH2,Naphthyl or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, OH, CN, N0 2 , NH 2 ,
1010
NHA, NA2, NH-Acyl, Acyl, -SA, -SOA, S02A, COOA oderNHA, NA 2 , NH-acyl, acyl, -SA, -SOA, S0 2 A, COOA or
Phenyl, X CH oder N,Phenyl, X CH or N,
Y S02 wenn X = N, oderY S0 2 if X = N, or
15 S, SO, S02 wenn X = CH,15 S, SO, S0 2 if X = CH,
Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, A, CN,Het 1 unsubstituted or single, double or triple by shark, A, CN,
CONH2, CH2COOA, Phenyl-S02, Acyl, OA oder OH substituiertes ungesättigtes heterocyclisches Ringsystem, ~0 welches eines, zwei oder drei gleiche oder verschiedeneCONH 2 , CH 2 COOA, phenyl-S0 2 , acyl, OA or OH substituted unsaturated heterocyclic ring system, ~ 0 which one, two or three identical or different
Heteroatome wie Stickstoff, Sauerstoff und Schwefel enthält,Contains heteroatoms such as nitrogen, oxygen and sulfur,
A Alkyl mit 1-6 C-Atomen, alk Alkylen mit 1-6 C-Atomen,A alkyl with 1-6 C atoms, alk alkylene with 1-6 C atoms,
Hai F, Cl, Br oder I,Shark F, Cl, Br or I,
25 bedeuten, sowie deren physiologisch unbedenklichen Salze und Solvate, als Arzneimittel mit 5-HT2A-Rezeptor-antagonistischer Wirkung.25 mean, as well as their physiologically acceptable salts and solvates, as a drug with 5-HT 2A receptor antagonistic effect.
,0 Gegenstand der Erfindung sind auch die Verbindungen der Formel I sowie deren Enantiomere sowie Diastereomere und deren Salze., 0 The present invention also provides the compounds of formula I and their enantiomers and diastereomers and salts thereof.
Für alle Reste, die mehrfach auftreten, wie z.B. A oder Hai, gilt, daß deren Bedeutungen unabhängig voneinander sind.For all residues that occur more than once, e.g. A or shark, their meanings are independent of each other.
35 Der Rest A bedeutet Alkyl und hat 1 bis 6 , vorzugsweise 1 , 2, 3 oder 4, insbesondere 1 oder 2 C-Atome. Alkyl bedeutet daher insbesondere z.B. Methyl, weiterhin Ethyl, n-Propyl, Isopropyl, n-Butyl, sek.-Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1 ,1-, 1 ,2- oder 2,2- Dimethylpropyl, 1-Ethylpropyl, Hexyl, 1-, 2-, 3- oder 4-Methylpentyl, 1 ,1-,35 The radical A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4, in particular 1 or 2, carbon atoms. Alkyl therefore means in particular, for example, methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1 , 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-,
1 ,2-, 1 ,3-, 2,2-, 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1- methylpropyl, 1-Ethyl-2-methylpropyl, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropyl. In den genannten Alkylresten können auch 1-7 H-Atome durch Fluor und/oder Chlor ersetzt sein. So bedeutet A z.B. auch Trifluormethyl oder Pentafluorethyl.1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1 , 1, 2- or 1, 2,2-trimethylpropyl. In the alkyl radicals mentioned, 1-7 H atoms can also be replaced by fluorine and / or chlorine. So A means e.g. also trifluoromethyl or pentafluoroethyl.
Acyl hat vorzugsweise 1-6 C-Atome und bedeutet z.B. Formyl, Acetyl, Propionyl, Butyryl, ferner Trifluoracetyl.Acyl preferably has 1-6 C atoms and means e.g. Formyl, acetyl, propionyl, butyryl, also trifluoroacetyl.
Alkylen hat 1 , 2, 3, 4, 5 oder 6 C-Atome, ist unverzweigt oder verzweigt und bedeutet vorzugsweise Methylen, Ethylen, Propylen, Butylen oderAlkylene has 1, 2, 3, 4, 5 or 6 carbon atoms, is unbranched or branched and preferably means methylene, ethylene, propylene, or butylene
Pentylen. Alkylen bedeutet ganz besonders bevorzugt Ethylen. OA ist vorzugsweise Methoxy, Trifluormethoxy, ferner auch Ethoxy, n-Propoxy, Isopropoxy, n-Butoxy, Isobutoxy, sek.-Butoxy oder tert.-Butoxy.Pentylene. Alkylene very particularly preferably means ethylene. OA is preferably methoxy, trifluoromethoxy, and also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
Hai bedeutet Fluor, Chlor, Brom oder lod, insbesondere Fluor oder Chlor.Shark means fluorine, chlorine, bromine or iodine, especially fluorine or chlorine.
R1 und R2 bedeuten jeweils unabhängig voneinander unsubstituiertes, vorzugsweise - wie angegeben - durch R3 und/oder R4 substituiertes Phenyl oder Naphthyl, im einzelnen bevorzugt Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethylphenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-R 1 and R 2 each independently represent unsubstituted, preferably - as indicated - substituted by R 3 and / or R 4 substituted phenyl or naphthyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-
Isopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Trifluor- methylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Nitrophenyl, o-, m- oder p-(Trifluormethoxy)-phenyl, o-, m- oder p-Cyanphenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-Isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p- (trifluoromethoxy) phenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl , o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-
(Difluormethoxy)-phenyl, o-, m- oder p-(Fluormethoxy)-phenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5- Dibromphenyl, 2-Chlor-3-methyl-, 2-Chlor-4-methyl-, 2-Chlor-5-methyl-, 2- Chlor-6-methyl-, 2-Methyl-3-chlor-, 2-Methyl-4-chlor-, 2-Methyl-5-chior-, 2-(Difluoromethoxy) phenyl, o-, m- or p- (fluoromethoxy) phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 -Difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2 , 6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl , 2-methyl-3-chloro, 2-methyl-4-chloro, 2-methyl-5-chloro, 2-
Methyl-6-chlor-, 3-Chlor-4-methyl-, 3-Chlor-5-methyl- oder 3-Methyl-4- chlorphenyl, 2-Brom-3-methyl-, 2-Brom-4-methyl-, 2-Brom-5-methyl-, 2- Brom-6-methyl-, 2-Methyl-3-brom-, 2-Methyl-4-brom-, 2-Methyl-5-brom-, 2- Methyl-6-brom-, 3-Brom-4-methyl-, 3-Brom-5-methyl- oder 3-Methyl-4- bromphenyl, 2,4- oder 2,5-Dinitrophenyl, 2,4- oder 3,4-Dimethoxyphenyl, 3-Nitro-4-chlorphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder 3,4,5-Tri- chlorphenyl, 2,4,6-tri-tert.-Butylphenyl, ferner bevorzugt 2-Nitro-4-(trifluor- methyl)phenyl, 3,5-Di-(trifluormethyl)-phenyl, 2,4-Dimethylphenyl, 2-Hydroxy-3,5-dichlorphenyl, 2-Fluor-5- oder 4-Fluor-3-(trifluormethyl)- phenyl, 4-Chlor-2- oder 4-Chlor-3-(trifluormethyl)-, 2-Chlor-4- oder 2-Chlor- 5-(trifluormethyl)-phenyl, 4-Brom-2- oder 4-Brom-3-(trifluormethyl)-phenyl, p-lodphenyl, 2-Nitro-4-methoxyphenyl, 2,5-Dimethoxy-4-nitrophenyl, 2-Methyl-5-nitrophenyl, 2,4-Dimethyl-3-nitrophenyl, 4-Fluor-3-chlorphenyl, 4-Fluor-3,5-dimethylphenyl, 2-Fluor-4-Bromphenyl, 2,5-Difluor-4- bromphenyl, 2,4-Dichlor-5-methylphenyl, 3-Brom-6-methoxyphenyl, 3- Chlor-6-methoxyphenyl, 2-Methoxy-5-methylphenyl oder 2,4,6-Methyl 6-chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4- chlorophenyl, 2-bromo-3-methyl, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl, 2-methyl-3-bromo, 2-methyl -4-bromo, 2-methyl-5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl, 3-bromo-5-methyl or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,4- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 2,3,4-, 2,3,5-, 2,3,6- , 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, further preferably 2-nitro-4- (trifluoromethyl) phenyl, 3,5- Di- (trifluoromethyl) phenyl, 2,4-dimethylphenyl, 2-hydroxy-3,5-dichlorophenyl, 2-fluoro-5- or 4-fluoro-3- (trifluoromethyl) phenyl, 4-chloro-2- or 4-chloro-3- (trifluoromethyl) -, 2-chloro-4- or 2-chloro-5- (trifluoromethyl) -phenyl, 4-bromo-2- or 4-bromo-3- (trifluoromethyl) -phenyl, p -lodphenyl, 2-nitro-4-methoxyphenyl, 2,5-dimethoxy-4-nitrophenyl, 2-methyl-5-nitrophenyl, 2,4-dimethyl-3-nitrophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro -3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3- Chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl or 2,4,6-
Thisopropylphenyl.Thisopropylphenyl.
R1 und R2 bedeuten auch jeweils unabhängig voneinander Het1. Het1 ist vorzugsweise 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3- Pyrrolyl, 1-, 2, 4- oder 5-lmidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oderR 1 and R 2 are each independently Het 1 . Het 1 is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or
5-Oxazolyl, 3-, 4- oder 5-lsoxazolyl, 2-, 4- oder 5-Thiazolyl, 3-, 4- oder 5- Isothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1 ,2,3-Thazol-1-, -4- oder -5-yl, 1 ,2,4-Triazol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1 ,2,3-Oxadiazol-4- oder -5-yl, 1 ,2,4-Oxadiazol-3- oder - 5-yl, 1 ,3,4-Thiadiazol-2- oder -5-yl, 1 ,2,4-Thiadiazol-3- oder -5-yl, 1 ,2,3-5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-thazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4-thiadiazol-2- or -5 -yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-
Thiadiazol-4- oder -5-yl, 2-, 3-, 4-, 5- oder 6-2H-Thiopyranyl, 2-, 3- oder 4- 4-H-Thiopyranyl, 3- oder 4-Pyridazinyl, Pyrazinyl, 2-, 3-, 4-, 5- 6- oder 7- Benzofuryl, 2-, 3-, 4-, 5-, 6- oder 7-Benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 1-, 2-, 4- oder 5-Benzimidazolyl, 1-, 3-, 4-, 5-, 6- oder 7-Benzo- pyrazolyl, 2-, 4-, 5-, 6- oder 7-Benzoxazolyl, 3-, 4-, 5-, 6- oder 7- Benzisox- azolyl, 2-, 4-, 5-, 6- oder 7-Benzthiazolyl, 2-, 4-, 5-, 6- oder 7-Benzisothi- azolyl, 4-, 5-, 6- oder 7-Benz-2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8- Chinolyl, 1-, 3-, 4-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, 4-, 5-, 6-, 7- oder 8- Cinnolinyl, 2-, 4-, 5-, 6-, 7- oder δ-Chinazolinyl, 1-, 2- ,3- oder 4- Dibenzofuranyl, ferner 3-Methyl-3H-imidazo[4,5-c]pyridin-4-yl, 1-Methyl- 1 H-imidazo[4,5-c]pyridin-4-yl, 1 (3)-H-imidazo[4,5-c]pyridin-4-yl, lmidazo[2,1-b]thiazol-5-yl, 2,3-Dihydro-1 H-lndolThiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4- 4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl , 2-, 3-, 4-, 5- 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4 -, 5-, 6-, 7- or δ-quinazolinyl, 1-, 2-, 3- or 4-dibenzofuranyl, furthermore 3-methyl-3H-imidazo [4,5-c] pyridin-4-yl, 1 -Methyl- 1 H-imidazo [4,5-c] pyridin-4-yl, 1 (3) -H-imidazo [4,5-c] pyridin-4-yl, imidazo [2,1-b] thiazol-5- yl, 2,3-dihydro-1H-indole
R1 bedeutet ganz besonders bevorzugt Phenyl, p-Chlorphenyl, p- Fluorphenyl,Thiophen-2-yl, 5-Chlor-thiophen-2-yl, 2,5-Dichlor-thiophen-3-yl und 2- oder 3-Furyl.R 1 very particularly preferably denotes phenyl, p-chlorophenyl, p-fluorophenyl, thiophene-2-yl, 5-chloro-thiophene-2-yl, 2,5-dichloro-thiophene-3-yl and 2- or 3-furyl ,
R2 bedeutet ganz besonders bevorzugt 4-Propylphenyl, 2-lsopropylphenyl, Butyl, 2,4,6-Trimethylphenyl, 2- oder 4-Methoxyphenyl, 2-, 3- oder 4- Methoxycarbonylphenyl, 2-, 3- oder 4-Ethoxycarbonylphenyl, 2- oder 4- Chlorphenyl, 2-Nitrophenyl, 4'-Biphenyl, 2,4,6-Trimethylphenyl, 3,4-R 2 very particularly preferably denotes 4-propylphenyl, 2-isopropylphenyl, butyl, 2,4,6-trimethylphenyl, 2- or 4-methoxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylphenyl , 2- or 4-chlorophenyl, 2-nitrophenyl, 4'-biphenyl, 2,4,6-trimethylphenyl, 3,4-
Dimethyiphenyl, 2-Naphthyl, 6-Chlor-2-naphthyl, 5-Chlor-1-naphthyl, 5- Dibutylamino-1-naphthyl, 4-lsopropylphenyl, 2-Thienyl, 2,1 ,3- Benzothiadiazol-4-yl, 4-Fluorphenyl, 2-Chlor-pyridin-6-yl, 3,4-Dimeth- oxyphenyl, 2,4-Dichlorphenyl, 4-Tolyl, 2,4- , 2,5- oder 3,4-Difluorphenyl, 2- Fluorphenyl, 2-Methoxy-pyridin-6-yl, Chinolin-8-yl, lsochinolin-1-yl, 5-Dimethyiphenyl, 2-naphthyl, 6-chloro-2-naphthyl, 5-chloro-1-naphthyl, 5-dibutylamino-1-naphthyl, 4-isopropylphenyl, 2-thienyl, 2,1, 3-benzothiadiazol-4-yl, 4-fluorophenyl, 2-chloro-pyridin-6-yl, 3,4-dimethoxyphenyl, 2,4-dichlorophenyl, 4-tolyl, 2,4-, 2,5- or 3,4-difluorophenyl, 2- Fluorophenyl, 2-methoxy-pyridin-6-yl, quinolin-8-yl, isoquinolin-1-yl, 5-
Acetamido-naphth-1-yl, 5-Dimethylamino-naphth-1-yl, Dibenzofuran-1-yl, Thiophen-2-yl, 4-Phenylsulfonyl-thiophen-2-yl, 4-Phenylsulfonyl-thiophen- 3-yl, 5-Chlor-3-methyl-benzo[b]thiophen-2-yl, Pyrimidin-2-yl, lndol-3- oder - 5-yl, 3-Cyan-indol-5-yl, Benzimidazol-2-yl, 1-Methyl-1 H-imidazol-2-yl, 1- Methyl-1 H-tetrazol-5-yi, 4-Methyl-4H-[1 ,2,4]-triazol-3-yl, 4,5-Dihydro- thiazol-2-yl, 2-Methoxycarbonylmethyl-thiazol-4-yl, Benzo[2,1 ,3]oxadiazol- 4-yl, 1-Acetyl-2,3-dihydro-lndol-5-yl, 2,3-Dihydro-1H-lndol-5-yl, 1-Methyl- 1 H-imidazol-4-yl, 1 -(3-Chlor-5-trifluormethyl-pyridin-2-yl)-pyrrol-3-yl,Acetamido-naphth-1-yl, 5-dimethylamino-naphth-1-yl, dibenzofuran-1-yl, thiophene-2-yl, 4-phenylsulfonylthiophene-2-yl, 4-phenylsulfonylthiophene-3-yl, 5-chloro-3-methyl-benzo [b] thiophene-2-yl, pyrimidin-2-yl, indol-3- or - 5-yl, 3-cyanoindol-5-yl, benzimidazol-2-yl, 1-methyl-1 H-imidazol-2-yl, 1-methyl-1 H-tetrazol-5-yi, 4-methyl-4H- [1, 2,4] -triazol-3-yl, 4,5- Dihydro-thiazol-2-yl, 2-methoxycarbonylmethyl-thiazol-4-yl, benzo [2,1, 3] oxadiazol-4-yl, 1-acetyl-2,3-dihydro-indol-5-yl, 2, 3-dihydro-1H-indol-5-yl, 1-methyl-1 H-imidazol-4-yl, 1 - (3-chloro-5-trifluoromethyl-pyridin-2-yl) pyrrol-3-yl,
Gegenstand der Erfindung sind auch die Verbindungen 4-{4-[2-(4-The invention also relates to the compounds 4- {4- [2- (4-
Fluorphenyl)-ethyl]-piperazin-1-sulfonyl}-2,1 ,3-Benzothiadiazol und 4-{4-[2- (4-Fluorphenyl)-ethyl]-piperazin-1-sulfonyl}-2,1 ,3-Benzoxadiazol.Fluorophenyl) ethyl] piperazin-1-sulfonyl} -2,1,3-benzothiadiazole and 4- {4- [2- (4-fluorophenyl) ethyl] piperazin-1-sulfonyl} -2,1,3 -Benzoxadiazol.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejeni- gen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln la bis Ik ausgedrückt werden, die der Formel I entsprechen und worin die nicht näher bezeichneten Reste die bei der Formel I angegebene Bedeutung haben, worin jedoch in la R einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1, bedeutet; in Ib R1 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest, bedeutet; in Ic R1 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest,Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following partial formulas Ia to Ik, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which in la R denotes a phenyl or naphthyl radical or Het 1 substituted by R 3 , R 4 and / or R 5 ; in Ib R 1 denotes a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 ; in Ic R 1 a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 ,
R2 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1, bedeutet; in Id R1 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest, R2 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1, Het1 unsubstituiertes oder ein- oder zweifach durch Hai, CN,R 2 represents a phenyl or naphthyl radical or Het 1 substituted by R 3 , R 4 and / or R 5 ; in Id R 1 is a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 , R 2 is a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 or Het 1 , Het 1 is unsubstituted or a - or twice by shark, CN,
Acyl, Phenyl-S02 oder A substituiertes ungesättigtes heterocyclisches Ringsystem, welches ein oder zwei gleiche oder verschiedene Heteroatome wie Stickstoff,Acyl, phenyl-S0 2 or A substituted unsaturated heterocyclic ring system which has one or two identical or different heteroatoms such as nitrogen,
Sauerstoff und Schwefel enthält, bedeutet; in le R1 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest,Contains oxygen and sulfur means; in le R 1 a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 ,
R2 einen durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1, Het1 unsubstituiertes oder ein- oder zweifach durch Hai, CN,R 2 is a phenyl or naphthyl radical substituted by R 3 , R 4 and / or R 5 or Het 1 , Het 1 unsubstituted or mono- or disubstituted by shark, CN,
Acyl, Phenyl-S02 oder A substituiertes Thienyl,Acyl, phenyl S0 2 or A substituted thienyl,
Dibenzofuranyl, Benzo[b]thiophenyl, Indolyl, Pyridinyl, Benzo[2,1 ,3]oxadiazol-4-yl, 2,3-Dihydro-1 H-lndol-5-yl, Imidazolyl oder 1 -(Pyridin-2-yl)-pyrrolyl, bedeutet; in If X CH,Dibenzofuranyl, benzo [b] thiophenyl, indolyl, pyridinyl, Benzo [2,1,3] oxadiazol-4-yl, 2,3-dihydro-1H-indol-5-yl, imidazolyl or 1 - (pyridin-2-yl) pyrrolyl; in If X CH,
R1 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest, R2 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1,R 1 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical, R 2 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical or Het 1 ,
R3, R4, R5 jeweils unabhängig voneinander Hai, CN, -SA, A,R 3 , R 4 , R 5 each independently of one another shark, CN, -SA, A,
COOA oder OA, Het1 unsubstituiertes oder ein- oder zweifach durch Hai, A oder CH2COOA substituiertes Thienyl, Chinolinyl,COOA or OA, Het 1 unsubstituted or mono- or disubstituted by shark, A or CH 2 COOA thienyl, quinolinyl,
Isochinolinyl, Dibenzofuranyl, Benzo[b]thiophenyl, Tetrazolyl, Triazolyl oder Imidazolyl, Pyridinyl, 4,5-Dihydro-thiazolyl, Pyrimidinyl, Benzimidazolyl oder Indolyl, bedeutet; in Ig X CH,Isoquinolinyl, dibenzofuranyl, benzo [b] thiophenyl, tetrazolyl, triazolyl or imidazolyl, pyridinyl, 4,5-dihydro-thiazolyl, pyrimidinyl, benzimidazolyl or indolyl; in Ig X CH,
R1 einen durch R3, R4 und/oder R5 substituiertenR 1 is substituted by R 3 , R 4 and / or R 5
Phenylrest, R2 einen durch R3, R4 und/oder R5 substituiertenPhenyl radical, R 2 is a substituted by R 3 , R 4 and / or R 5
Phenylrest,phenyl,
R3, R4, R5 jeweils unabhängig voneinander Hai, CN, -SA, A,R 3 , R 4 , R 5 each independently of one another shark, CN, -SA, A,
COOA oder OA, alk Alkylen mit 1-4 C-Atomen, bedeutet; in Ih X N,COOA or OA, alk alkylene with 1-4 C atoms means; in Ih X N,
R1 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest, R2 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1 , R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, NH2, NHA, ■* NA2, NH-Acyl, Acyl oder Phenyl,R 1 is a phenyl or naphthyl radical which is unsubstituted or substituted by R 3 , R 4 and / or R 5 , R 2 is an unsubstituted or substituted by R 3 , R 4 and / or R 5 phenyl or naphthyl radical or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, NH 2 , NHA, ■ * NA 2 , NH-acyl, acyl or phenyl,
Het1 unsubstituiertes oder ein- oder zweifach durch Hai, CN,Het 1 unsubstituted or single or double by shark, CN,
Acyl, Phenyl-S02 oder A substituiertes ungesättigtes heterocyclisches Ringsystem, welches ein oder zwei 10 gleiche oder verschiedene Heteroatome wie Stickstoff,Acyl, phenyl-S0 2 or A substituted unsaturated heterocyclic ring system which has one or two 10 identical or different heteroatoms such as nitrogen,
Sauerstoff und Schwefel enthält, bedeutet; in li X N,Contains oxygen and sulfur means; in li X N,
, - R1 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest, R2 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest oder Het1 , R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, NH2, NHA,, - R 1 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical, R 2 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical or Het 1 , R 3 , R 4 , R 5 each independently of one another shark, A, OA, NH 2 , NHA,
NA2, NH-Acyl, Acyl oder Phenyl, Het1 unsubstituiertes oder ein- oder zweifach durch Hai, CN,NA 2 , NH-acyl, acyl or phenyl, Het 1 unsubstituted or mono- or disubstituted by shark, CN,
Acyl, Phenyl-S02 oder A substituiertes Thienyl, 25 Dibenzofuranyl, Benzo[b]thiophenyl, Indolyl, Pyridinyl,Acyl, phenyl SO 2 or A substituted thienyl, 25 dibenzofuranyl, benzo [b] thiophenyl, indolyl, pyridinyl,
Benzo[2, 1 ,3]oxadiazol-4-yl, 2,3-Dihydro-1 H-lndol-5-yl, imidazolyl oder 1 -(Pyridin-2-yl)-pyrrolyl, bedeutet; 30 in Ij X N,Benzo [2, 1, 3] oxadiazol-4-yl, 2,3-dihydro-1H-indol-5-yl, imidazolyl or 1 - (pyridin-2-yl) pyrrolyl; 30 in Ij X N,
R1 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest, R2 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oder Naphthylrest 33 oder Het1 , R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, NH2, NHA, NA2, NH-Acyl, Acyl oder Phenyl,R 1 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical, R 2 is an unsubstituted or R 3 , R 4 and / or R 5 substituted phenyl or naphthyl radical 33 or Het 1 , R 3 , R 4 , R 5 are each independently of one another shark, A, OA, NH 2 , NHA, NA 2 , NH-acyl, acyl or phenyl,
Het1 unsubstituiertes oder ein- oder zweifach durch Hai, CN,Het 1 unsubstituted or single or double by shark, CN,
Acyl, Phenyl-S02 oder A substituiertes Thienyl, Dibenzofuranyl, Benzo[b]thiophenyl, Indolyl, Pyridinyl, Benzo[2,1 ,3]oxadiazol-4-yl, 2,3-Dihydro-1 H-indol-5-yl, Imidazolyl oder 1-(Pyridin-2-yl)-pyrrolyl, bedeutet; in Ik X CH oder N,Acyl, phenyl-S0 2 or A substituted thienyl, dibenzofuranyl, benzo [b] thiophenyl, indolyl, pyridinyl, benzo [2,1, 3] oxadiazol-4-yl, 2,3-dihydro-1 H-indol-5- yl, imidazolyl or 1- (pyridin-2-yl) pyrrolyl; in Ik X CH or N,
R1 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenylrest,R 1 is an unsubstituted or substituted by R 3 , R 4 and / or R 5 ,
R2 einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten PhenylrestR 2 is a phenyl radical which is unsubstituted or substituted by R 3 , R 4 and / or R 5
R3, R4, R5 jeweils unabhängig voneinander Hai, A, COOA oder OA, alk Alkylen mit 1-4 C-Atomen bedeutet;R 3 , R 4 , R 5 each independently represent shark, A, COOA or OA, alk alkylene with 1-4 C atoms;
wobei Het1 ≠2,1 ,3-Benzoxadiazol- oder 2,1 ,3-Benzothiadiazol-yl, sowie deren physiologisch unbedenklichen Salze und Solvate.where Het 1 ≠ 2,1, 3-benzoxadiazol- or 2,1, 3-benzothiadiazol-yl, and their physiologically acceptable salts and solvates.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrerThe compounds of formula I and also the starting materials for their
Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in Standardwerken wie Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York;) beschrieben sind, und zwar unter Reaktionsbedingungen, wie sie für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.Manufacture is otherwise produced according to methods known per se, as described in the literature (for example in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; ) are described, namely under reaction conditions as are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
Die Ausgangsstoffe für das beanspruchte Verfahren können gewünschten- falls auch in situ gebildet werden, derart, dass man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt. Andererseits ist es möglich, die Reaktion stufenweise durchzuführen.If desired, the starting materials for the claimed process can also be formed in situ in such a way that they are not isolated from the reaction mixture, but instead are immediately passed on to the compounds of Formula I implements. On the other hand, it is possible to carry out the reaction in stages.
In den Verbindungen der Formel III und V ist der Rest L vorzugsweise Cl oder Br; er kann jedoch auch 1, OH oder auch bevorzugt eine reaktionsfähig funktionell abgewandelte OH-Gruppe bedeuten, insbesondere Alkylsulfonyloxy mit 1-6 (z.B. Methansulfonyloxy) oder Aryisulfonyloxy mit 6-10 C-Atomen (z.B. Benzolsulfonyloxy, p-Toluolsulfonyloxy, 1- oder 2- Naphthalinsulfonyloxy) oder auch Trichlormethoxy, Alkoxy, wie z.B. Methoxy, Ethoxy, Propoxy oder Butoxy, ferner auch Phenoxy.In the compounds of the formula III and V, the radical L is preferably Cl or Br; however, it can also mean 1, OH or, preferably, a reactive, functionally modified OH group, in particular alkylsulfonyloxy with 1-6 (e.g. methanesulfonyloxy) or aryisulfonyloxy with 6-10 C atoms (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2 - Naphthalenesulfonyloxy) or trichloromethoxy, alkoxy, such as Methoxy, ethoxy, propoxy or butoxy, also phenoxy.
Die Verbindungen der Formel I, worin X N bedeutet, können vorzugsweise erhalten werden, indem man Verbindungen der Formel II mit Verbindungen der Formel III umsetzt.The compounds of the formula I in which X is N can preferably be obtained by reacting compounds of the formula II with compounds of the formula III.
Die Ausgangsstoffe der Formeln II und III sind in der Regel bekannt; die nicht bekannten Verbindungen der Formeln II und III können leicht analog zu den bekannten Verbindungen hergestellt werden.The starting materials of formulas II and III are generally known; the unknown compounds of formulas II and III can easily be prepared analogously to the known compounds.
Die Umsetzung der Verbindungen II und III verläuft nach Methoden, wie sie für die Alkylierung bzw. Acylierung von Aminen aus der Literatur bekannt sind. Es ist aber auch möglich, die Verbindungen in Gegenwart eines indifferenten Lösungsmittels umzusetzen. Als Lösungsmittel eignen sich z.B. Kohlenwasserstoffe, wie Benzol, Toluol, Xylol; Ketone wie Aceton, Butanon; Alkohole wie Methanol, Ethanol, Isopropanol, N-Butanol;The reaction of the compounds II and III proceeds according to methods known from the literature for the alkylation or acylation of amines. However, it is also possible to react the compounds in the presence of an inert solvent. Suitable solvents are e.g. Hydrocarbons such as benzene, toluene, xylene; Ketones such as acetone, butanone; Alcohols such as methanol, ethanol, isopropanol, N-butanol;
Ether wie Tetrahydrofuran (THF) oder Dioxan; Amide wie Dimethylform- amid (DMF) oder N-Methyl-pyrrolidon; Nitrile wie Acetonitril, gegebenenfalls auch Gemische dieser Lösungsmittel untereinander oder Gemische mit Wasser. Der Zusatz eines säurebindenden Mittels, beispielsweise eines Alkali- oder Erdalkaiimetallhydroxids, -carbonats oder -bicarbonats oder eines anderen Salzes einer schwachen Säure der Alkali- oder Erdalkalimetalle, vorzugsweise des Kaliums, Natriums oder Calciums, oder der Zusatz einer organischen Base wie Triethylamin, Dimethylaniiin, Pyridin oder Chinolin oder eines Überschusses Piperazin-Derivates der Formel II kann günstig sein. Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reak- tionstemperatur zwischen etwa 0 und 150°, normalerweise zwischen 20 und 130°.Ethers such as tetrahydrofuran (THF) or dioxane; Amides such as dimethylformamide (DMF) or N-methylpyrrolidone; Nitriles such as acetonitrile, optionally also mixtures of these solvents with one another or mixtures with water. The addition of an acid-binding agent, for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium or calcium, or the addition of an organic base such as triethylamine, dimethylaniiine, Pyridine or quinoline or an excess of piperazine derivative of formula II may be beneficial. Depending on the conditions used, the reaction time is between a few minutes and 14 days. tion temperature between about 0 and 150 °, usually between 20 and 130 °.
Desweiteren kann man Verbindungen der Formel I, worin X CH bedeutet, herstellen, indem man Amine der Formel IV mit einer Komponente der Formel V umsetzt, und das Reaktionsprodukt anschließend oxidiert. Bei der Oxidation entsteht in der Regel ein Gemisch aus Sulfinyl- und Sulfonylverbindung, das chromatographisch oder durch Kristallisation in die Einzelverbindungen aufgetrennt werden kann.Furthermore, compounds of the formula I in which X is CH can be prepared by reacting amines of the formula IV with a component of the formula V and then oxidizing the reaction product. The oxidation generally produces a mixture of sulfinyl and sulfonyl compounds, which can be separated into the individual compounds by chromatography or by crystallization.
Die jeweiligen Komponenten sind in der Regel bekannt oder können wie schon beschrieben nach bekannten Verfahren hergestellt werden. Die Umsetzung zwischen den Verbindungen der Formel IV und V verlaufen unter Bedingungen wie für die Umsetzung zwischen den Verbindungen der Formel II und III beschrieben.The respective components are generally known or, as already described, can be produced by known processes. The reaction between the compounds of the formula IV and V proceeds under conditions as described for the reaction between the compounds of the formula II and III.
Eine erhaltene Base der Formel I kann mit einer Säure in das zugehörige Säureadditionssalz übergeführt werden. Für diese Umsetzung eignen sich Säuren, die physiologisch unbedenkliche Salze liefern. So können anor- ganische Säuren verwendet werden, z.B. Schwefelsäure, Halogenwasserstoffsäuren wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Salpetersäure, Sulfaminsäure, ferner organische Säuren, im einzelnen aliphatische, alicyclische, arali- phatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, wie Ameisensäure, Essigsäure,A base of the formula I obtained can be converted into the associated acid addition salt using an acid. Acids which provide physiologically acceptable salts are suitable for this reaction. Inorganic acids can be used, e.g. Sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, acetic acid
Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Benzoesäure, Salicylsäure, 2-Phenylpropionsäure, Citronen- säure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2-Hydroxyethan- sulfonsäure; Benzolsulfonsäure, p-Toluolsulfonsäure, Naphthalin-mono- und -disulfonsäuren, Laurylschwefelsäure.Propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotonic acid, methane -Hydroxyethanesulfonic acid; Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid.
Die freien Basen der Formel I können, falls gewünscht, aus ihren Salzen durch Behandlung mit starken Basen wie Natrium- oder Kaliumhydroxid,If desired, the free bases of the formula I can be obtained from their salts by treatment with strong bases such as sodium or potassium hydroxide,
Natrium- oder Kaliumcarbonat in Freiheit gesetzt werden, sofern keine weiteren aciden Gruppen im Molekül vorliegen. In jenen Fällen, wo die Verbindungen der Formel I über freie Säuregruppen verfügen, kann durch Behandlung mit Basen ebenfalls eine Salzbildung erreicht werden. Als Basen eignen sich Alkalimetallhydroxide, Erdalkalimetallhydroxide oder organische Basen in Form von primären, sekundären oder tertiärenSodium or potassium carbonate are released, if none other acidic groups in the molecule. In those cases where the compounds of formula I have free acid groups, salt formation can also be achieved by treatment with bases. Suitable bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary
Aminen.Amines.
Gegenstand der Erfindung sind weiterhin die erfindungsgemäßen Arzneimittel mit 5-HT2A-Rezeptor-antagonistischer Wirkung zur Behandlung von Psychosen, Schizophrenie, Depression, neurologischen Störungen,The invention furthermore relates to the medicaments according to the invention with 5-HT 2A receptor antagonistic activity for the treatment of psychoses, schizophrenia, depression, neurological disorders,
Gedächtnisstörungen, Morbus Parkinson, amyotropher Lateralsklerose, der Alzheimer Krankheit, der Huntington Krankheit, Essstörungen wie Bulimie, nervöser Anorexie, des prämenstrualen Syndroms und/oder zur positiven Beeinflussung von Zwangsverhalten (obsessive-compulsive disorder, OCD).Memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders such as bulimia, nervous anorexia, premenstrual syndrome and / or to positively influence compulsive behavior (obsessive-compulsive disorder, OCD).
Gegenstand der Erfindung ist auch eine pharmazeutische Zubereitung, enthaltend mindestens ein erfindungsgemäßes Arzneimittel sowie gegebenenfalls Träger- und/oder Hilfsstoffe und gegebenenfalls andere Wirkstoffe.The invention also relates to a pharmaceutical preparation containing at least one medicament according to the invention and, if appropriate, carriers and / or auxiliaries and, if appropriate, other active compounds.
Hierbei können die Arzneimittel zusammen mit mindestens einem festen, flüssigen und/oder halbflüssigen Träger- oder Hilfsstoff und gegebenenfalls in Kombination mit einem oder mehreren weiteren Wirkstoff(en) in eine geeignete Dosierungsform gebracht werden.The medicinal products can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
Gegenstand der Erfindung ist weiterhin die Verwendung der erfindungsgemäßen Verbindungen und/oder von deren physiologisch unbedenklichen Salzen und Solvaten zur Herstellung eines Arzneimittels mit 5-HT2A- Rezeptor-antagonistischer Wirkung.The invention furthermore relates to the use of the compounds according to the invention and / or of their physiologically acceptable salts and solvates for the production of a medicament with 5-HT 2A - receptor-antagonistic activity.
Gegenstand der Erfindung ist auch die Verwendung der erfindungsgemäßen Verbindungen und/oder von deren physiologisch unbedenklichen Salzen und Solvaten zur Herstellung eines Arzneimittels mit 5-HTz^- Rezeptor-antagonistischer Wirkung zur Behandlung von Psychosen, Schizophrenie, Depression, neurologischen Störungen, Gedächtnisstörungen, Morbus Parkinson, amyotropher Lateralsklerose, der Alzheimer Krankheit, der Huntington Krankheit, Essstörungen wie Bulimie, nervöser Anorexie, des prämenstrualen Syndroms und/oder zur positiven Beeinflussung von Zwangsverhalten (obsessive-compulsive disorder, OCD).The invention also relates to the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament with 5-HTz ^ - receptor-antagonistic activity for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease , amyotrophic lateral sclerosis, Alzheimer's Disease, Huntington's disease, eating disorders such as bulimia, nervous anorexia, premenstrual syndrome and / or to positively influence compulsive behavior (obsessive-compulsive disorder, OCD).
Die pharmazeutischen Zubereitungen können als Arzneimittel in der Human- und Veterinärmedizin eingesetzt werden. Als Trägersubstanzen kommen organische oder anorganische Stoffe in Frage, die sich für die enterale (z.B. orale), parenterale oder topische Applikation eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohoie, Polyethylenglykole, Gelatine, Kohlehydrate wie Lactose oder Stärke, Magnesiumstearat, Talk, Vaseline. Zur enteralen Applikation dienen insbesondere Tabletten, Dragees, Kapseln, Sirupe, Säfte, Tropfen oder Suppositoren, zur parenteralen Applikation Lösungen, vorzugsweise ölige oder wässrige Lösungen, ferner Suspensionen,The pharmaceutical preparations can be used as pharmaceuticals in human and veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohol, polyethylene glycols, gelatin, carbohydrates such as lactose or starch , Magnesium stearate, talc, petroleum jelly. Tablets, coated tablets, capsules, syrups, juices, drops or suppositories are used in particular for enteral administration, solutions, preferably oily or aqueous solutions, and further suspensions are used for parenteral administration.
Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenden Lyophilisate z.B. zur Herstellung von Injektionspräparaten verwendet werden.Emulsions or implants, for topical application of ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables.
Die angegebenen Zubereitungen können sterilisiert sein und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Färb-, Geschmacks- und/oder Aromastoffe enthalten. Sie können, falls erwünscht, auch einen oder mehrere weitere Wirkstoffe enthalten, z.B. ein oder mehrere Vitamine.The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavors and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. one or more vitamins.
Dabei werden die erfindungsgemäßen Substanzen in der Regel in Analogie zu bekannten Präparaten verabreicht, vorzugsweise in Dosierungen zwischen etwa 0,1 und 500 mg, insbesondere zwischen 5 und 300 mg pro Dosierungseinheit. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,01 und 250 mg/kg, insbesondere zwischen 0,02 und 100 mg/kg Körpergewicht.The substances according to the invention are generally administered in analogy to known preparations, preferably in doses between about 0.1 and 500 mg, in particular between 5 and 300 mg per dosage unit. The daily dosage is preferably between about 0.01 and 250 mg / kg, in particular between 0.02 and 100 mg / kg body weight.
Dabei werden die erfindungsgemäßen Substanzen in der Regel vorzugsweise in Dosierungen zwischen etwa 1 und 500 mg, insbesondere zwischen 5 und 100 mg pro Dosierungseinheit verabreicht. Die tägliche Dosierung liegt vorzugsweise zwischen etwa 0,02 und 10 mg/kg Körpergewicht. Die spezielle Dosis für jeden bestimmten Patienten hängt jedoch von den verschiedensten Faktoren ab, beispielsweise von der Wirksamkeit der eingesetzten speziellen Verbindung, vom Alter, Körpergewicht, allgemeinen Gesundheitszustand, Geschlecht, von der Kost, vom Verabfol- gungszeitpunkt und -weg, von der Ausscheidungsgeschwindigkeit, Arzneistoffkombination und Schwere der jeweiligen Erkrankung, welcher die Therapie gilt. Die orale Applikation ist bevorzugt.The substances according to the invention are generally preferably used in doses between about 1 and 500 mg, in particular administered between 5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each particular patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion, Drug combination and severity of the disease to which the therapy applies. Oral application is preferred.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachstehenden Beispielen bedeutet "übliche Aufarbeitung": Man entfernt, falls erforderlich, das Lösungsmittel, gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetat oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, filtriert, engt ein und reinigt durch Chromatographie an Kieselgel und/oder durch Kristallisation.All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, the solvent is removed, water is added if necessary and, if necessary, the pH is adjusted to between 2 and 10, depending on the constitution of the end product, extracted with ethyl acetate or dichloromethane, separates, the organic phase dries over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel and / or by crystallization.
Beispiel A1Example A1
Herstellung einer Suspension von 5-HT2A Rezeptoren:Preparation of a suspension of 5-HT 2A receptors:
Frontaler Rattencortex wird in eiskaltem Puffer homogenisiert. DasFrontal rat cortex is homogenized in ice-cold buffer. The
Homogenat wird 10 Minuten bei 4°C und 50000 X zentrifugiert. Das Pellet wird in 2,5 ml eiskaltem Trispuffer resuspendiert, mit 10 ml zusätzlichemHomogenate is centrifuged at 4 ° C and 50000 X for 10 minutes. The pellet is resuspended in 2.5 ml ice-cold Tris buffer, with an additional 10 ml
Puffer aufgefüllt und wie beschrieben zentrifugiert. Danach wird das Pellet in Puffer resuspendiert und zu einem Homogenat verdünnt, das 60 mg Material/ml enthält. In die Inkubationsröhrchen werden 0,1 ml der Suspension, 100 μl einer 5 nM Lösung von [3H]Ketanserin, 100 μl einer Lösung der TestverbindungBuffer filled and centrifuged as described. The pellet is then resuspended in buffer and diluted to a homogenate containing 60 mg material / ml. 0.1 ml of the suspension, 100 μl of a 5 nM solution of [ 3 H] ketanserin, 100 μl of a solution of the test compound are placed in the incubation tube
(Konzentration im Bereich von 10"5 bis 10"10 Mol pro Liter) gegeben und mit Puffer auf 1 ml aufgefüllt. Die Röhrchen werden 15 Minuten bei 37 °C inkubiert. Nach Abbrechen der Inkubation durch Eintauchen der Röhrchen in ein Eisbad wird die gekühlte Suspension durch ein Glasfilter unter Vakuum filtriert. Die Filter werden 3x mit 5 ml kaltem Puffer gewaschen und dann in Szintillationsröhrchen überführt. Die Filter werden mittels Flüssigszintillations-Spektrometrie in 8 ml Triton-X-Szintillatorflüssigkeit analysiert.(Concentration in the range of 10 "5 to 10 " 10 mol per liter) and made up to 1 ml with buffer. The tubes are incubated at 37 ° C for 15 minutes. After the incubation has been terminated by immersing the tubes in an ice bath, the cooled suspension is filtered through a glass filter under vacuum. The filters are washed 3 times with 5 ml of cold buffer and then transferred to scintillation tubes. The filters are by means of Liquid scintillation spectrometry analyzed in 8 ml Triton-X scintillator liquid.
TesterqebnisseTesterqebnisse
1. 4-(8-Chinolin-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid: IC50 (5-HT^) = 1 ,3 nM/L.1. 4- (8-quinoline-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride: IC50 (5-HT ^) = 1.3 nM / L.
2. 4-(1-Naphthyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid: IC50 (5-HT2A) = 8,1 nM/L.2. 4- (1-Naphthylsulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride: IC50 (5-HT2A) = 8.1 nM / L.
3. 4-(4-Fluorphenyl-suifonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid: IC50 (5-HT^) = 25,0 nM/L.3. 4- (4-fluorophenyl-suifonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride: IC50 (5-HT ^) = 25.0 nM / L.
4. 4-(5-Acetamido-naphth-1 -yl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid: IC50 (5-HT^) = 7,4 nM/L.4. 4- (5-Acetamido-naphth-1-yl-sulfonyl) -1 - [2- (4-fluorophenyl) -ethyl] - piperazine, hydrochloride: IC50 (5-HT ^) = 7.4 nM / L ,
5. 4-(2,1 ,3-Benzoxadiazol-4-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid: IC50 (5-HT^) = 44,0 nM/L.5. 4- (2,1, 3-Benzoxadiazol-4-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride: IC50 (5-HT ^) = 44.0 nM / L.
6. 4-(2-Nitrophenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid: IC50 (5-HT^) = 9,2 nM/L.6. 4- (2-nitrophenylsulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride: IC50 (5-HT ^) = 9.2 nM / L.
7. 4-(2,3-Dihydro-1 H-indol-5-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid: IC50 (5-HT2A) = 13,0 nM/L.7. 4- (2,3-Dihydro-1H-indole-5-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride: IC50 (5-HT 2A ) = 13.0 nM / L.
8. 4-(3-Cyan-1 H-indol-5-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperazin: IC50 (5-HT2A) = 1 ,6 nM/L8. 4- (3-Cyan-1H-indole-5-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperazine: IC50 (5-HT 2A ) = 1.6 nM / L
9. 4-(4-Fluorphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid: IC50 (5-HT2A) = 2,1 nM/L.9. 4- (4-fluorophenylsulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride: IC50 (5-HT 2A ) = 2.1 nM / L.
10. 2-Chlor-6-{1 -[2-(4-fluorphenyl)-ethyl]-piperidin-4-sulfonyl}-pyridin, Hydrochlorid: IC50 (5-HT2A) = 0,6 nM/L. Synthesebeispiele:10. 2-Chloro-6- {1 - [2- (4-fluorophenyl) ethyl] piperidine-4-sulfonyl} pyridine, hydrochloride: IC50 (5-HT2A) = 0.6 nM / L. Synthesis Examples:
Beispiel 1example 1
Eine Lösung von 590 g BOC-(tert.-Butyloxycarbonyl)-Piperazin und 700 g Methansuifonsäure-2-(4-fluor-phenyl)-ethylester in 10 Liter Aceton itril wird bei 40° portionsweise mit 840 g NaHCθ3 versetzt und anschließend 12 Stunden unter Rückfluß erhitzt. Nach Abkühlen und Filtration wird wie üblich aufgearbeitet. Man erhält 1013 g 1-BOC-4-[2-(4-Fluoro-phenyl)- ethylj-piperazin, F. 68-70°.A solution of 590 g of BOC- (tert-butyloxycarbonyl) piperazine and 700 g of methanesuifonic acid 2- (4-fluorophenyl) ethyl ester in 10 liters of acetone itril is mixed with 840 g of NaHCO 3 in portions at 40 ° and then for 12 hours heated under reflux. After cooling and filtration, the mixture is worked up as usual. 1013 g of 1-BOC-4- [2- (4-fluoro-phenyl) ethylj-piperazine, mp 68-70 ° are obtained.
Man löst die Verbindung in 1500 ml Dioxan und versetzt mit 400 ml ethanolischer Salzsäure. Man erhitzt 12 Stunden unter Rückfluß. Nach Abkühlen werden die ausgefallenen Kristalle abgetrennt, mit Dioxan gewaschen und getrocknet. Man erhält 440g 1-[2-(4-Fluoro-phenyl)-ethyl]- piperazin, Dihydrochlorid, ("AB"), F. 272-274°.The compound is dissolved in 1500 ml of dioxane and 400 ml of ethanolic hydrochloric acid are added. The mixture is heated under reflux for 12 hours. After cooling, the precipitated crystals are separated off, washed with dioxane and dried. 440 g of 1- [2- (4-fluorophenyl) ethyl] piperazine, dihydrochloride, ("AB"), mp 272-274 ° are obtained.
2,0 g "AB" und 1 ,78 g 8-Chlorsulfonyl-chinolin werden in 100 ml Dichlor- methan gelöst, mit 6,0 g polymergebundenem 4-Dimethylaminopyridin2.0 g of "AB" and 1.78 g of 8-chlorosulfonyl-quinoline are dissolved in 100 ml of dichloromethane, with 6.0 g of polymer-bound 4-dimethylaminopyridine
(DMAP auf Polystyrol) versetzt und 24 Stunden bei Raumtemperatur gerührt. Nach Filtration und üblicher Aufarbeitung erhält man 1 ,2 g 4-(8-Chinolin-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid, F. 141 °.(DMAP on polystyrene) and stirred for 24 hours at room temperature. After filtration and usual work-up, 1.2 g of 4- (8-quinoline-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 141 ° are obtained.
Analog erhält man die nachstehenden VerbindungenThe following compounds are obtained analogously
4-(4-Propylphenyl-sulfonyl)-1-(2-phenyl-ethyl)-piperazin, 4-(Butylsulfonyl)-1-(2-phenyl-ethyl)-piperazin, 4-(4-Methoxyphenyl-sulfonyl)-1 -(2-phenyl-ethyl)-piperazin, 4-(4-Chlorphenyl-sulfonyl)-1 -(2-phenyl-ethyl)-piperazin, 4-(4-Methoxyphenyl-sulfonyl)-1-(2-phenyl-ethyl)-piperazin, 4-(Biphenyl-4-sulfonyl)-1-(2-phenyl-ethyl)-piperazin, 4-(2,4,6-Thmethylphenyl-sulfonyl)-1-(2-phenyl-ethyl)-piperazin, 4-(2-Phenyl-ethen-sulfonyl)-1 -(2-phenyl-ethyl)-piperazin,4- (4-propylphenylsulfonyl) -1- (2-phenyl-ethyl) piperazine, 4- (butylsulfonyl) -1- (2-phenyl-ethyl) piperazine, 4- (4-methoxyphenylsulfonyl) - 1 - (2-phenyl-ethyl) -piperazine, 4- (4-chlorophenylsulfonyl) -1 - (2-phenyl-ethyl) -piperazine, 4- (4-methoxyphenylsulfonyl) -1- (2-phenyl -ethyl) -piperazine, 4- (biphenyl-4-sulfonyl) -1- (2-phenyl-ethyl) -piperazine, 4- (2,4,6-thmethylphenyl-sulfonyl) -1- (2-phenyl-ethyl ) -piperazine, 4- (2-phenyl-ethenesulfonyl) -1 - (2-phenyl-ethyl) -piperazine,
4-(3-Chlor-4-methylphenyl-sulfonyl)-1 -(2-phenyl-ethyl)-piperazin, 4-(2-Naphthyl-suifonyl)-1-(2-phenyl-ethyi)-piperazin,4- (3-chloro-4-methylphenylsulfonyl) -1 - (2-phenyl-ethyl) piperazine, 4- (2-naphthyl-suifonyl) -1- (2-phenyl-ethyl) -piperazine,
4-(6-Chlor-naphth-2-yl-sulfonyl)-1-(2-phenyl-ethyl)-piperazin,4- (6-chloro-naphth-2-yl-sulfonyl) -1- (2-phenyl-ethyl) -piperazine,
4-(4-Methoxyphenyl-sulfonyl)-1-[2-(3,5-dimethoxyphenyl)-ethyl]-piperazin,4- (4-methoxyphenyl-sulfonyl) -1- [2- (3,5-dimethoxyphenyl) ethyl] piperazine,
4-(4-lsopropylphenyl-sulfonyl)-1-[2-(3,5-dimethoxyphenyl)-ethyl]-piperazin, 4-(Biphenyl-4-sulfonyl)-1-[2-(3,5-dimethoxyphenyl)-ethyl]-piperazin,4- (4-isopropylphenylsulfonyl) -1- [2- (3,5-dimethoxyphenyl) ethyl] piperazine, 4- (biphenyl-4-sulfonyl) -1- [2- (3,5-dimethoxyphenyl) ethyl] piperazine,
4-(2-Naphthyl-sulfonyl)-1-[2-(3,5-dimethoxyphenyl)-ethyl]-piperazin,4- (2-naphthyl-sulfonyl) -1- [2- (3,5-dimethoxyphenyl) ethyl] piperazine,
4-(6-Chlor-Naphth-2-yi-sulfonyl)-1-[2-(3,5-dimethoxyphenyl)-ethyl]- piperazin,4- (6-chloro-naphth-2-yi-sulfonyl) -1- [2- (3,5-dimethoxyphenyl) ethyl] piperazine,
4-(2-Thienyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid, F. 226-228°;4- (2-thienylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 226-228 °;
4-(1-Naphthyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid,4- (1-naphthylsulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride,
F. 231 °;F. 231 °;
4-(2,1 ,3-Benzothiadiazol-4-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (2,1, 3-benzothiadiazol-4-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 207°; 4-(4-Fluorphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,Hydrochloride, mp 207 °; 4- (4-fluorophenyl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 237°;Hydrochloride, mp 237 °;
4-(5-Acetamido-naphth-1-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (5-Acetamido-naphth-1-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 243°;Hydrochloride, mp 243 °;
4-(5-Dimethylamino-naphth-1-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid;4- (5-dimethylamino-naphth-1-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride;
4-(5-Chlor-naphth-1-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (5-Chloro-naphth-1-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 241°;Hydrochloride, mp 241 °;
4-(Dibenzofuran-1-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (Dibenzofuran-1-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 216-217°; 4-(5-Chlor-3-methyl-benzo[b]thiophen-2-yl-sulfonyl)-1-[2-(4-fluorphenyl)- ethyl]-piperazin, Hydrochlorid, F. 250°;Hydrochloride, m.p. 216-217 °; 4- (5-chloro-3-methyl-benzo [b] thiophene-2-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 250 °;
4-(5-Dibutylamino-naphth-1-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid, F. 191 °;4- (5-dibutylamino-naphth-1-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 191 °;
4-(2,1 ,3-Benzoxadiazol-4-yl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid, F. 21 1-212°;4- (2,1, 3-benzoxadiazol-4-yl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, m.p. 21 1-212 °;
4-(2,5-Difluorphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (2,5-difluorophenyl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 244-247°;Hydrochloride, mp 244-247 °;
4-(2-Nitrophenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (2-nitrophenyl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 213-214°; 4-(2-Aminophenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,Hydrochloride, mp 213-214 °; 4- (2-aminophenyl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Dihydrochlorid/Hydrat, F. 211-215°; 4-(3-Cyan-1 H-indol-5-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin;Dihydrochloride / hydrate, mp 211-215 °; 4- (3-cyano-1H-indole-5-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine;
4-(4-Phenylsuifonyl-thiophen-2-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid, F. 188-192°; 4-(4-Phenylsulfonyl-thiophen-3-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid, F. 158-159°;4- (4-phenylsulfonyl-thiophene-2-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 188-192 °; 4- (4-phenylsulfonylthiophene-3-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 158-159 °;
4-(2-Nitrophenyi-suifonyi)-1-[2-(4-fluorphenyl)-ethyi]-piperazin,4- (2-nitrophenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] piperazine,
Hydrochlorid, F. 213-214°;Hydrochloride, mp 213-214 °;
4-(5-Brom-6-chlor-pyridin-3-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid, F. 242-243°;4- (5-bromo-6-chloropyridine-3-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 242-243 °;
4-(2-Aminophenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (2-aminophenyl-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Dihydrochlorid/Hydrat, F. 211-215°;Dihydrochloride / hydrate, mp 211-215 °;
4-(6-Chlor-imidazo[2,1 -b]thiazol-5-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperazin, Hydrochlorid, F. 247-248°; 4-(1 -Acetyl-2,3-dihydro-indol-5-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperazin, F. 177-179°;4- (6-chloro-imidazo [2,1 -b] thiazole-5-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 247-248 °; 4- (1-acetyl-2,3-dihydro-indole-5-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] - piperazine, mp 177-179 °;
4-(2,3-Dihydro-1 H-indol-5-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin,4- (2,3-dihydro-1H-indole-5-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine,
Hydrochlorid, F. 238-240°;Hydrochloride, mp 238-240 °;
4-(lndol-5-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperazin, Hydrochlorid, F. 246-248°;4- (indole-5-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, mp 246-248 °;
4-(1 -Methyl-1 H-imidazol-4-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperazin;4- (1-methyl-1 H -imidazole-4-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperazine;
4-[1-(3-Chlor-5-trifluormethyl-pyridin-2-yl)-pyrrol-3-sulfonyl)]-1-[2-(4- fluorphenyl)-ethyl]-piperazin, Hydrochlorid, F. 239-243°;4- [1- (3-chloro-5-trifluoromethyl-pyridin-2-yl) pyrrole-3-sulfonyl)] - 1- [2- (4-fluorophenyl) ethyl] piperazine, hydrochloride, F. 239 -243 °;
4-(lsochinolin-5-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperazin, Dihydrochlorid, F. 243-244°. 4- (isoquinoline-5-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine, dihydrochloride, mp 243-244 °.
Beispiel 1 aExample 1 a
Nach folgendem Schema erhält man 4-(3-Cyan-1 H-indol-5-sulfonyl)-1-[2-According to the following scheme, 4- (3-cyano-1H-indole-5-sulfonyl) -1- [2-
(4-fluorphenyl)-ethyl]-piperazin, F. 199-202°.(4-fluorophenyl) ethyl] piperazine, mp 199-202 °.
Die Synthese der Ausgangsmaterialien ist beschrieben in J. Org. ChemThe synthesis of the starting materials is described in J. Org. Chem
53, 2047-2052 (1988).53, 2047-2052 (1988).
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000025_0002
Figure imgf000025_0002
Mangandioxid
Figure imgf000025_0003
manganese dioxide
Figure imgf000025_0003
Figure imgf000025_0004
Beispiel 1 b
Figure imgf000025_0004
Example 1 b
Nach folgendem Schema erhält man 4-(3-Cyan-1 H-indol-7-sulfonyl)-1-[2- (4-fluorphenyl)-ethyl]-piperazin.The following scheme gives 4- (3-cyano-1H-indole-7-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperazine.
Figure imgf000026_0001
Figure imgf000026_0001
Toluoltoluene
Figure imgf000026_0002
Figure imgf000026_0002
Mangandioxidmanganese dioxide
Figure imgf000026_0003
Beispiel 2
Figure imgf000026_0003
Example 2
Eine Lösung von 500 mg 2-Chlor-6-(piperidin-4-ylsulfanyl)-pyridin, Hydro- Chlorid, 500 mg Methansuifonsäure-2-(4-fluor-phenyl)-ethylester und 500 mg NaHC03 wird 12 Stunden bei 80° gerührt. Nach Abkühlen wird wie üblich aufgearbeitet. Man erhält 610 mg 2-Chior-6-{1-[2-(4-fluor-phenyl)- ethyl]-piperidin-4-ylsulfanyl}-pyridin, Hydrochlorid ("AC") F. 237-240°.A solution of 500 mg of 2-chloro-6- (piperidin-4-ylsulfanyl) pyridine, hydrochloride, 500 mg of methanesulfonic acid 2- (4-fluorophenyl) ethyl ester and 500 mg of NaHC0 3 is 12 hours at 80 ° stirred. After cooling, working up as usual. 610 mg of 2-chloro-6- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} pyridine, hydrochloride ("AC") mp 237-240 ° are obtained.
Analog erhält man die VerbindungenThe connections are obtained analogously
2-Chlor-6-{1-[2-(2-fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-pyridin,2-chloro-6- {1- [2- (2-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} -pyridine,
Hydrochlorid, F. 182-184°;Hydrochloride, mp 182-184 °;
2-Chlor-6-{1-[2-(2-trifluormethyl-phenyl)-ethyl]-piperidin-4-ylsulfanyl}- pyridin, Hydrochlorid, F. 186-187°;2-chloro-6- {1- [2- (2-trifluoromethylphenyl) ethyl] piperidin-4-ylsulfanyl} pyridine, hydrochloride, mp 186-187 °;
2-Chlor-6-[1-(2-o-tolyl-ethyl)-piperidin-4-ylsulfanyl]-pyridin, Hydrochlorid, F.2-chloro-6- [1- (2-o-tolyl-ethyl) -piperidin-4-ylsulfanyl] pyridine, hydrochloride, F.
196-197°;196-197 °;
4-(4-Fluorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-fluorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 195-196°; 4-(4-Fluorphenyl-sulfanyl)-1-[2-(2-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 195-196 °; 4- (4-fluorophenyl-sulfanyl) -1- [2- (2-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 203-205°;Hydrochloride, mp 203-205 °;
4-(4-Fluorphenyl-sulfanyl)-1-[2-(2,4-difluorphenyl)-ethyl]-piperidin,4- (4-fluorophenyl-sulfanyl) -1- [2- (2,4-difluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 204-206°;Hydrochloride, mp 204-206 °;
4-Phenyl-sulfanyl-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 209- 211 °;4-phenylsulfanyl-1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 209-211 °;
Naphthalin-2-yl-sulfanyl-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,Naphthalin-2-yl-sulfanyl-1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride,
F. 190-192°;F. 190-192 °;
4-(4-Methoxyphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-methoxyphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 217-219°; 4-(3,4-Dimethoxyphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 217-219 °; 4- (3,4-dimethoxyphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 160-163°;Hydrochloride, mp 160-163 °;
4-(2,4-Dichlorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2,4-dichlorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 201-203°;Hydrochloride, mp 201-203 °;
4-p-Tolyl-sulfanyl-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 216- 218°; 6-Methoxy-2-{1-[2-(4-fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-pyridin,4-p-tolylsulfanyl-1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 216-218 °; 6-Methoxy-2- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} -pyridine,
Hydrochlorid, F. 207-209°;Hydrochloride, mp 207-209 °;
4-(4-Trifluormethoxyphenyl-sulfanyl)-1-[2-(4-fiuorphenyl)-ethyl]-piperidin,4- (4-trifluoromethoxyphenyl-sulfanyl) -1- [2- (4-fiuorphenyl) -ethyl] -piperidine,
Hydrochlorid, F. 188-189°; 4-(2,4-Difluorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 188-189 °; 4- (2,4-difluorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 200-202°;Hydrochloride, mp 200-202 °;
4-(4-Trifluormethylphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-trifluoromethylphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 193-195°;Hydrochloride, mp 193-195 °;
4-(2-Methoxyphenyl-suifanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 223-226°;4- (2-methoxyphenyl-suifanyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 223-226 °;
4-(4-tert.-Butylphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-tert-butylphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 208-211 °;Hydrochloride, mp 208-211 °;
4-(2-Fluorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2-fluorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 209-210°; 4-(2-Fluorphenyl-sulfanyl)-1 -[2-(2,4-difluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 209-210 °; 4- (2-fluorophenylsulfanyl) -1 - [2- (2,4-difluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 194-198°;Hydrochloride, mp 194-198 °;
4-(2-Fluorphenyl-sulfanyl)-1-[2-(3,4-difluorphenyl)-ethyl]-piperidin,4- (2-fluorophenyl-sulfanyl) -1- [2- (3,4-difluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 179-181°;Hydrochloride, mp 179-181 °;
2-{1-[2-(4-Fluor-phenyi)-ethyl]-piperidin-4-ylsulfanyl}-pyridin, Hydrochlorid, F. 243-245°;2- {1- [2- (4-fluorophenyi) ethyl] piperidin-4-ylsulfanyl} pyridine, hydrochloride, mp 243-245 °;
4-(4-Methylsulfanyl-phenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-methylsulfanyl-phenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 204-207°;Hydrochloride, mp 204-207 °;
4-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-benzonitril,4- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} benzonitrile,
Hydrochlorid, F. 206-207°; 4-(2,3-Dichlorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 206-207 °; 4- (2,3-dichlorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 197-199°;Hydrochloride, mp 197-199 °;
8-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-chinolin, F. 88-90°;8- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} quinoline, mp 88-90 °;
4-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-pyridin,4- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} -pyridine,
Dihydrochiorid; 2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-benzothiazol,dihydrochloride; 2- {1- [2- (4-fluorophenyl) -ethyl] -piperidin-4-ylsulfanyl} -benzothiazole,
Hydrochlorid, F. 217-218°;Hydrochloride, m.p. 217-218 °;
4-(2,4-Dimethoxyphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2,4-dimethoxyphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 210-212°;Hydrochloride, mp 210-212 °;
2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-chinoiin, Hydrochlorid, F. 257-259°; 4-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-7-trifluormethyl- chinolin, Dihydrochlorid, F. 137-140°;2- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} quinoiin, hydrochloride, mp 257-259 °; 4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -7-trifluoromethyl-quinoline, dihydrochloride, mp 137-140 °;
4-o-Tolyl-sulfanyl-1-[2-(4-fluorphenyl)-ethyi]-piperidin, Hydrochlorid, F. 201-4-o-tolylsulfanyl-1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, F. 201-
203°; 4-o-Tolyl-sulfanyl-1-[2-(2-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 225-203 °; 4-o-tolylsulfanyl-1- [2- (2-fluorophenyl) ethyl] piperidine, hydrochloride, m.p. 225-
229°;229 °;
4-o-Toiyi-sulfanyl-1 -[2-(2,4-difiuorphenyl)-ethyl]-piperidin, Hydrochlorid, F.4-o-Toiyi-sulfanyl-1 - [2- (2,4-difiuorphenyl) ethyl] piperidine, hydrochloride, F.
217-220°;217-220 °;
4-(2,4-Dimethylphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 228-230°;4- (2,4-dimethylphenylsulfanyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 228-230 °;
4-(2,4-Dimethylphenyl-sulfanyl)-1-[2-(2-fluorphenyl)-ethyl]-piperidin,4- (2,4-dimethylphenyl-sulfanyl) -1- [2- (2-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 229-231°;Hydrochloride, mp 229-231 °;
4-(2,4-Dimethylphenyl-sulfanyl)-1 -[2-(2,4-difluorphenyl)-ethyl]-piperidin,4- (2,4-dimethylphenylsulfanyl) -1 - [2- (2,4-difluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 248-250°; 4-(Thiazol-2-yl-sulfanyl)-1-[2-(4-fiuorphenyl)-ethyl]-piperidin, Hydrochlorid,Hydrochloride, mp 248-250 °; 4- (thiazol-2-yl-sulfanyl) -1- [2- (4-fiuorphenyl) ethyl] piperidine, hydrochloride,
F. 177-182°;Mp 177-182 °;
2-Chlor-6-{1-[2-(5-chlor-thiophen-2-yl)-ethyl]-piperidin-4-ylsulfanyl}-pyridin,2-chloro-6- {1- [2- (5-chloro-thiophen-2-yl) -ethyl] -piperidin-4-ylsulfanyl} -pyridine,
Hydrochlorid, F. 204-207°;Hydrochloride, mp 204-207 °;
4-{1-[2-(5-Chlor-thiophen-2-yl)-ethyl]-piperidin-4-ylsulfanyl}-benzonitril, Hydrochlorid, F. 174-175°;4- {1- [2- (5-chlorothiophen-2-yl) ethyl] piperidin-4-ylsulfanyl} benzonitrile, hydrochloride, mp 174-175 °;
2-Chlor-6-{1-[2-(4-fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-pyridin,2-chloro-6- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} -pyridine,
Hydrochlorid, F. 237-240°;Hydrochloride, mp 237-240 °;
2-{1 -[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-1 H-benzimidazol, Hydrochlorid, F. 234-235°;2- {1 - [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1 H-benzimidazole, hydrochloride, mp 234-235 °;
4-(Thiophen-2-yl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (thiophen-2-yl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Dihydrochlorid/Hydrat, F. 213-214°;Dihydrochloride / hydrate, mp 213-214 °;
4-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-phenol, Hydrochlorid,4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} phenol, hydrochloride,
F. 196-199°; 2-{1 -[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-phenol, Hydrochlorid,F. 196-199 °; 2- {1 - [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} phenol, hydrochloride,
F. 190-192°;F. 190-192 °;
3-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-1 H-indol,3- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1 H-indole,
Hydrochlorid, F. 135°;Hydrochloride, mp 135 °;
2-{1-[2-(4-Fluor-phenyl)-ethyi]-piperidin-4-ylsulfanyl}-pyrimidin, Hydrochlorid, F. 205-209°; 4-(1 -Methyl-1 H-imidazol-2-yl-sulfanyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin,2- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} pyrimidine, hydrochloride, mp 205-209 °; 4- (1-methyl-1 H-imidazol-2-yl-sulfanyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 193-197°;Hydrochloride, mp 193-197 °;
4-(4,5-Dihydro-thiazol-2-yl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4,5-dihydro-thiazol-2-yl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Dihydrochlorid/Hydrat; 4-(2-Chlorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Dihydrochloride / hydrate; 4- (2-chlorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 205-207°;Hydrochloride, mp 205-207 °;
4-(4-Chlorphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-chlorophenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 220-221 °;Hydrochloride, mp 220-221 °;
4-(2-Methoxyphenyl-sulfanyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidin, Hydrochlorid, F. 205-207°;4- (2-methoxyphenylsulfanyl) -1- [2- (4-methoxyphenyl) ethyl] piperidine, hydrochloride, mp 205-207 °;
4-(2-lsopropylphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2-isopropylphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 203-205°;Hydrochloride, mp 203-205 °;
2-{1-[2-(2,4-Difluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-phenol,2- {1- [2- (2,4-difluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} phenol,
Hydrochlorid, F. 92°; 2-{1-[2-(2-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-phenol, F. 80°;Hydrochloride, mp 92 °; 2- {1- [2- (2-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} phenol, mp 80 °;
2-{1-[2-(3,4-Difluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-phenol, F. 100°;2- {1- [2- (3,4-difluorophenyl) ethyl] piperidin-4-ylsulfanyl} phenol, mp 100 °;
4-(2-Ethylphenyl-sulfanyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin, F. 200-203°;4- (2-ethylphenylsulfanyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, mp 200-203 °;
4-(1 -Methyl-1 H-tetrazol-5-yl-sulfanyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin,4- (1-methyl-1 H-tetrazol-5-yl-sulfanyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 193-195°; 4-(2,4,6-Trimethylphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 193-195 °; 4- (2,4,6-trimethylphenyl-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 248-250°;Hydrochloride, mp 248-250 °;
4-(4-Methyl-4H-[1 ,2,4]-triazol-3-yl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]- piperidin, Hydrochlorid, F. >260°;4- (4-methyl-4H- [1,2,4] -triazol-3-yl-sulfanyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp> 260 °;
8-{1-[2-(2,4-Difluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-chinolin, Hydrochlorid, F. 153-160°;8- {1- [2- (2,4-difluorophenyl) ethyl] piperidin-4-ylsulfanyl} quinoline, hydrochloride, mp 153-160 °;
8-[1-(2-Naphthalin-2-yl-ethyl)-piperidin-4-ylsulfanyl]-chinolin,8- [1- (2-naphthalen-2-yl-ethyl) -piperidin-4-ylsulfanyl] quinoline,
Dihydrochlorid/Hydrat, F. 217-219°;Dihydrochloride / hydrate, mp 217-219 °;
8-[1-(2-Naphthalin-1-yl-ethyl)-piperidin-4-ylsulfanyl]-chinolin,8- [1- (2-naphthalen-1-yl-ethyl) -piperidin-4-ylsulfanyl] quinoline,
Dihydrochlorid/Hydrat, F. 214-222°; 2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-benzoesäure- ethylester, Dihydrochlorid/Hydrat, F. 171-174°;Dihydrochloride / hydrate, mp 214-222 °; Ethyl 2- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} benzoate, dihydrochloride / hydrate, mp 171-174 °;
1-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-isochinolin,1- {1- [2- (4-fluorophenyl) -ethyl] -piperidin-4-ylsulfanyl} -isoquinoline,
Hydrochlorid, F. 282°;Hydrochloride, mp 282 °;
2-{1-[2-(2,4-Dichlor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-phenol, Dihydrochlorid, F. 254-259°; 2-[1-(2-Naphthalin-2-yl-ethyl)-piperidin-4-ylsulfanyl]-phenol, Hydrochlorid,2- {1- [2- (2,4-dichlorophenyl) ethyl] piperidin-4-ylsulfanyl} phenol, dihydrochloride, mp 254-259 °; 2- [1- (2-naphthalen-2-yl-ethyl) piperidin-4-ylsulfanyl] phenol, hydrochloride,
F. 125°;F. 125 °;
4-(4-Acetylphenyi-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-Acetylphenyi-sulfanyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 208-210°; 8-{1-[2-(2-Chlor-4-fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-chinolin,Hydrochloride, mp 208-210 °; 8- {1- [2- (2-chloro-4-fluorophenyl) -ethyl] -piperidin-4-ylsulfanyl} quinoline,
Hydrochlorid, F. 145-155°;Hydrochloride, mp 145-155 °;
4-(2-Methoxycarbonylmethyl-thiazol-4-yl-sulfanyl)-1-[2-(4-fluorphenyl)- ethylj-piperidin, Dihydrochlorid/Hydrat, F. 139-142°;4- (2-methoxycarbonylmethylthiazol-4-yl-sulfanyl) -1- [2- (4-fluorophenyl) ethylj-piperidine, dihydrochloride / hydrate, mp 139-142 °;
4-(2-Acetylphenyl-sulfanyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 182-183°;4- (2-acetylphenylsulfanyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 182-183 °;
2-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfanyl}-6-methyl-pyridin,2- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfanyl} -6-methyl-pyridine,
Hydrochlorid, F. 250-255°;Hydrochloride, mp 250-255 °;
2-{1-[2-(2,4-Difluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-1 H-benzimidazol,2- {1- [2- (2,4-difluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1 H-benzimidazole,
Dihydrochlorid/Dihydrat, F. 247-248°; 4-(2-Methoxyphenyl-sulfanyl)-1 -[2-(2,4-difiuorfluorphenyl)-ethyl]-piperidin,Dihydrochloride / dihydrate, mp 247-248 °; 4- (2-methoxyphenylsulfanyl) -1 - [2- (2,4-difiuorfluorophenyl) ethyl] piperidine,
Dihydrochlorid, F. 229-231 °;Dihydrochloride, mp 229-231 °;
2-{1-[2-(2-Chlor-4-fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-1 H- benzimidazol, Hydrochlorid;2- {1- [2- (2-chloro-4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1 H -benzimidazole, hydrochloride;
2-{1-[2-(2-Fluorphenyl)-ethyl]-piperidin-4-yisulfanyl}-1 H-benzimidazol, Dihydrochlorid, F. 190-194°;2- {1- [2- (2-fluorophenyl) ethyl] piperidin-4-yisulfanyl} -1 H-benzimidazole, dihydrochloride, mp 190-194 °;
4-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-3-methyl-3H- imidazo[4,5-c]pyridin, Dihydrochlorid/Hydrat, F. >250°;4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -3-methyl-3H-imidazo [4,5-c] pyridine, dihydrochloride / hydrate, mp> 250 °;
4-(1 H-lndol-3-yl-sulfanyl)-1-[2-(2,4-difluorphenyl)-ethyl]-piperidin,4- (1 H-indol-3-yl-sulfanyl) -1- [2- (2,4-difluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 150°; 4-(1 H-lndol-3-yl-sulfanyl)-1-[2-(2-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,Hydrochloride, mp 150 °; 4- (1 H-indol-3-yl-sulfanyl) -1- [2- (2-fluorophenyl) ethyl] piperidine, hydrochloride,
F. 190-193°;F. 190-193 °;
4-(1 H-lndol-3-yl-sulfanyl)-1-[2-(o-tolyl)-ethyl]-piperidin, Hydrochlorid, F.4- (1 H-indol-3-yl-sulfanyl) -1- [2- (o-tolyl) ethyl] piperidine, hydrochloride, F.
200°;200 °;
4-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-1-methyl-1 H- imidazo[4,5-c]pyridin, Dihydrochlorid, F. >280°;4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1-methyl-1 H-imidazo [4,5-c] pyridine, dihydrochloride, mp> 280 °;
4-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-1 H-imidazo[4,5- φyridin, Trihydrochlorid, F. >280°;4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1 H -imidazo [4,5- φyridine, trihydrochloride, mp> 280 °;
4-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-2-methyl-1 H- imidazo[4,5-c]pyridin, Trihydrochlorid, F. >145-152°; 2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfanyl}-1 H-imidazo[4,5- bjpyridin, Dihydrochlorid, F. 65-69°. Beispiel 34- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -2-methyl-1 H -imidazo [4,5-c] pyridine, trihydrochloride, mp> 145-152 ° ; 2- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfanyl} -1 H-imidazo [4,5-bpyridine, dihydrochloride, mp 65-69 °. Example 3
Eine Lösung von 390 mg "AC" in 2,5 ml Eisessig wird bei Raumtemperatur mit 0,25 ml Wasserstoffperoxid (30 %ig) versetzt und 12 Stunden nachgerührt. Nach üblicher Aufarbeitung erhält man 245 mg 2-Chlor-6-{1- [2-(4-fiuorphenyi)-ethyl]-piperidin-4-suifinyl}-pyridin, Hydrochlorid, F. 208° und 60 mg 2-Chlor-6-{1-[2-(4-fluorphenyl)-ethyl]-piperidin-4-sulfonyl}- pyridin, Hydrochlorid, F. 208°.A solution of 390 mg "AC" in 2.5 ml glacial acetic acid is mixed with 0.25 ml hydrogen peroxide (30%) at room temperature and stirred for 12 hours. After customary working up, 245 mg of 2-chloro-6- {1- [2- (4-fiuorphenyi) ethyl] piperidine-4-suifinyl} pyridine, hydrochloride, melting point 208 ° and 60 mg of 2-chloro 6- {1- [2- (4-fluorophenyl) ethyl] piperidine-4-sulfonyl} pyridine, hydrochloride, mp 208 °.
Analog erhält man die nachstehenden VerbindungenThe following compounds are obtained analogously
4-(4-Fluorphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,4- (4-fluorophenylsulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride,
F. 225°; 4-(4-Fluorphenyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin,F. 225 °; 4- (4-fluorophenylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 243°;Hydrochloride, mp 243 °;
4-(4-Fluorphenyl-sulfonyl)-1-[2-(2-fluorphenyl)-ethyl]-piperidin,4- (4-fluorophenyl-sulfonyl) -1- [2- (2-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 240°;Hydrochloride, mp 240 °;
4-(4-Fluorphenyl-sulfonyl)-1-[2-(2,4-difluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 253°;4- (4-fluorophenylsulfonyl) -1- [2- (2,4-difluorophenyl) ethyl] piperidine, hydrochloride, mp 253 °;
4-(Phenyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F.4- (phenylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, F.
246-247°;246-247 °;
4-(Phenyl-sulfinyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F.4- (phenylsulfinyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, F.
222-224°; 4-(2-Naphthyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F.222-224 °; 4- (2-naphthylsulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, F.
197-199°;197-199 °;
4-(2-Naphthyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,4- (2-naphthylsulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride,
F. 253-255°;Mp 253-255 °;
4-(4-Methoxyphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 228-230°;4- (4-methoxyphenylsulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 228-230 °;
4-(4-Methoxyphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-methoxyphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 232-234°;Hydrochloride, mp 232-234 °;
4-(3,4-Dimethoxyphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (3,4-dimethoxyphenyl-sulfinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 180-182°; 4-(3,4-Dimethoxyphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 180-182 °; 4- (3,4-dimethoxyphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 194-195°; 4-(2,4-Dichlorphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 194-195 °; 4- (2,4-dichlorophenyl-sulfinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 220-223°;Hydrochloride, mp 220-223 °;
4-(2,4-Dichlorphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2,4-dichlorophenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 271-275°; 4-(4-Tolyl-sulfinyi)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F.Hydrochloride, mp 271-275 °; 4- (4-tolylsulfinyi) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, F.
223-224°;223-224 °;
4-(4-Toiyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F.4- (4-toylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, F.
265-267°;265-267 °;
4-(2,4-Difluorphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 222-223°;4- (2,4-difluorophenylsulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 222-223 °;
4-(2,4-Difluorphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2,4-difluorophenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 240-241°;Hydrochloride, mp 240-241 °;
4-(2-Fluorphenyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2-fluorophenylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 228-230°; 4-(2-Fluorphenyl-sulfonyl)-1 -[2-(2,4-difluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 228-230 °; 4- (2-fluorophenylsulfonyl) -1 - [2- (2,4-difluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 249-251 °;Hydrochloride, mp 249-251 °;
4-(2-Fluorphenyl-sulfonyl)-1-[2-(3,4-difluorphenyl)-ethyl]-piperidin,4- (2-fluorophenyl-sulfonyl) -1- [2- (3,4-difluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 203-205°;Hydrochloride, mp 203-205 °;
6-Methoxy-2-{1-[2-(4-fluor-phenyl)-ethyl]-piperidin-4-ylsulfonyl}-pyridin, Hydrochlorid, F. 202-203°;6-methoxy-2- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfonyl} pyridine, hydrochloride, mp 202-203 °;
6-Methoxy-2-{1-[2-(4-fluor-phenyl)-ethyl]-piperidin-4-ylsulfinyl}-pyridin,6-Methoxy-2- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfinyl} pyridine,
Hydrochlorid, F. 186-188°;Hydrochloride, mp 186-188 °;
4-(2-Fluorphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,4- (2-fluorophenylsulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride,
F. 200-202°; 4-(2-Fluorphenyl-sulfinyl)-1-[2-(2,4-difluorphenyl)-ethyl]-piperidin,F. 200-202 °; 4- (2-fluorophenyl-sulfinyl) -1- [2- (2,4-difluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 183-185°;Hydrochloride, mp 183-185 °;
4-(2-Fluorphenyl-sulfinyl)-1-[2-(3,4-difluorphenyl)-ethyl]-piperidin,4- (2-fluorophenyl-sulfinyl) -1- [2- (3,4-difluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 191-193°;Hydrochloride, mp 191-193 °;
4-(4-Trifluormethylphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 270-272°;4- (4-trifluoromethylphenylsulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 270-272 °;
4-(4-Trifluormethylphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-trifluoromethylphenyl-sulfinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 218-219°;Hydrochloride, mp 218-219 °;
4-(4-Trifluormethoxyphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-trifluoromethoxyphenyl-sulfinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 210-211 °; 4-(4-Trifluormethoxyphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 210-211 °; 4- (4-trifluoromethoxyphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 249-251 °; 4-(2-Methoxyphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 249-251 °; 4- (2-methoxyphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 245-247°;Hydrochloride, mp 245-247 °;
4-(2-Methoxyphenyl-sulfιnyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2-methoxyphenyl sulfιnyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 208-210°; 4-(4-tert.-Butylphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 208-210 °; 4- (4-tert-butylphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 274-276°;Hydrochloride, mp 274-276 °;
4-(4-tert.-Butylphenyl-sulfinyl)-1-[2-(4-fιuorphenyl)-ethyi]-piperidin,4- (4-tert-butylphenyl-sulfinyl) -1- [2- (4-fιuorphenyl) -ethyl] -piperidine,
Hydrochlorid, F. 226-228°;Hydrochloride, mp 226-228 °;
4-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfonyl}-benzonitril, Hydrochlorid, F. > 260°;4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfonyl} benzonitrile, hydrochloride, mp> 260 °;
2-{l-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfonyl}-pyridin, Hydrochlorid,2- {l- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfonyl} pyridine, hydrochloride,
F. 228-230°;F. 228-230 °;
2-{l-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfinyl}-pyridin, Hydrochlorid,2- {l- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfinyl} pyridine, hydrochloride,
F. 205-210°; 4-(2,3-Dichlorphenyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-piperidin,F. 205-210 °; 4- (2,3-dichlorophenylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine,
Hydrochlorid, F. 272-273°;Hydrochloride, mp 272-273 °;
4-(2,3-Dichlorphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2,3-dichlorophenyl-sulfinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 227-228°;Hydrochloride, mp 227-228 °;
4-(2-Fluor-phenylmethan-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 268-270°;4- (2-fluorophenylmethanesulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 268-270 °;
4-(2-Fluor-phenylmethan-sulfιnyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2-fluoro-phenylmethane-sulfιnyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 198-199°;Hydrochloride, mp 198-199 °;
4-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfonyl}-pyridin,4- {1- [2- (4-fluoro-phenyl) -ethyl] -piperidin-4-ylsulfonyl} pyridine,
Dihydrochlorid, F. 228-240°; 4-{1-[2-(4-Fluor-phenyl)-ethyl]-piperidin-4-ylsulfinyl}-pyridin, Dihydrochlorid,Dihydrochloride, mp 228-240 °; 4- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfinyl} pyridine, dihydrochloride,
F. 166-170°;M. 166-170 °;
8-{i-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfonyl}-chinolin, Hydrochlorid,8- {i- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfonyl} quinoline, hydrochloride,
F. 255-265°;F. 255-265 °;
8-{l-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-yisulfinyl}-chinolin, Hydrochlorid, F. 210°;8- {l- [2- (4-fluorophenyl) ethyl] piperidin-4-yisulfinyl} quinoline, hydrochloride, mp 210 °;
6-{i-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfonyi}-nicotinamid,6- {I- [2- (4-fluorophenyl) -ethyl] -piperidin-4-ylsulfonyi} -nicotinamide,
Hydrochlorid;Hydrochloride;
4-(4-Methansuifinylphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-Methansuifinylphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 180-185°; 2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsulfonyl}-chinolin, Hydrochlorid,Hydrochloride, mp 180-185 °; 2- {1- [2- (4-fluorophenyl) ethyl] piperidin-4-ylsulfonyl} quinoline, hydrochloride,
F. 238-240°; 2-{1 -[2-(4-Fluorphenyl)-ethyl]-piperidin-4-ylsuifinyl}-chinolin, Hydrochlorid,F. 238-240 °; 2- {1 - [2- (4-fluorophenyl) ethyl] piperidin-4-ylsuifinyl} quinoline, hydrochloride,
F. 210-213°;F. 210-213 °;
4-(2,4-Dimethoxyphenyl-suifinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (2,4-dimethoxyphenyl-suifinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 208-210°; 4-(2,4-Dimethoxyphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 208-210 °; 4- (2,4-dimethoxyphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 238°;Hydrochloride, mp 238 °;
2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-yisulfonyl}-benzothiazol,2- {1- [2- (4-fluorophenyl) -ethyl] -piperidin-4-yisulfonyl} -benzothiazole,
Hydrochlorid, F. 233-234°;Hydrochloride, mp 233-234 °;
4-(4-Methansulfinylphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 180-185°;4- (4-methanesulfinylphenylsulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 180-185 °;
4-[2-(4-Phenylsulfonyl-piperidin-1-yl)-ethyl]-pyridin, Dihydrochlorid, F. 187-4- [2- (4-phenylsulfonylpiperidin-1-yl) ethyl] pyridine, dihydrochloride, m.p. 187-
193°;193 °;
4-[2-(4-Phenylsulfinyl-piperidin-1-yl)-ethyl]-pyridin, Dihydrochlorid, F. 153-4- [2- (4-phenylsulfinyl-piperidin-1-yl) ethyl] pyridine, dihydrochloride, m.p. 153-
155°; 4-{2-[4-(3,4-Dimethoxyphenyl-sulfonyl)-piperidin-1 -yl]-ethyl}-pyridin,155 °; 4- {2- [4- (3,4-dimethoxyphenylsulfonyl) piperidin-1-yl] ethyl} pyridine,
Dihydrochlorid, F. 125-135°;Dihydrochloride, mp 125-135 °;
4-{2-[4-(3,4-Dimethoxyphenyi-sulfinyl)-piperidin-1-yl]-ethyl}-pyridin,4- {2- [4- (3,4-dimethoxyphenyl-sulfinyl) -piperidin-1-yl] ethyl} pyridine,
Dihydrochlorid, F. 149-155°;Dihydrochloride, mp 149-155 °;
4-{2-[4-(Tolyl-4-sulfinyl)-piperidin-1 -yl]-ethyl}-pyridin, Dihydrochlorid, F. 210-214°;4- {2- [4- (tolyl-4-sulfinyl) piperidin-1-yl] ethyl} pyridine, dihydrochloride, mp 210-214 °;
4-{2-[4-(2-Methoxyphenyl-sulfonyl)-piperidin-1-yl]-ethyl}-pyridin,4- {2- [4- (2-methoxyphenyl-sulfonyl) piperidin-1-yl] ethyl} pyridine,
Dihydrochlorid, F. 200-218°;Dihydrochloride, mp 200-218 °;
4-{2-[4-(2-Methoxyphenyl-suifinyi)-piperidin-1-yl]-ethyl}-pyridin,4- {2- [4- (2-methoxyphenyl-sulfinyl) -piperidin-1-yl] ethyl} pyridine,
Dihydrochlorid, F. 214-222°; 4-{1 -[2-(5-Chlor-thiophen-2-yl)-ethyl]-piperidin-4-ylsulfonyl}-benzonitril,Dihydrochloride, mp 214-222 °; 4- {1 - [2- (5-chlorothiophen-2-yl) ethyl] piperidin-4-ylsulfonyl} benzonitrile,
Hydrochlorid, F. > 250°;Hydrochloride, mp> 250 °;
4-{1-[2-(5-Chlor-thiophen-2-yl)-ethyl]-piperidin-4-ylsulfinyl}-benzonitril,4- {1- [2- (5-chloro-thiophen-2-yl) -ethyl] -piperidin-4-ylsulfinyl} -benzonitrile,
Hydrochlorid, F. 200-202°;Hydrochloride, mp 200-202 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2-methyiphenyl-sulfonyl)-piperidin,1- [2- (4-fluorophenyl) ethyl] -4- (2-methylphenyl-sulfonyl) -piperidine,
Hydrochlorid, F. 221-223°;Hydrochloride, mp 221-223 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2-methylphenyl-sulfinyl)-piperidin,1- [2- (4-fluorophenyl) ethyl] -4- (2-methylphenyl-sulfinyl) piperidine,
Hydrochlorid, F. 214-216°;Hydrochloride, mp 214-216 °;
1-[2-(2-Fluorphenyl)-ethyl]-4-(2-methylphenyl-sulfonyl)-piperidin, Hydrochlorid, F. 218-221 °; 1-[2-(2-Fluorphenyl)-ethyl]-4-(2-methylphenyl-sulfinyl)-piperidin,1- [2- (2-fluorophenyl) ethyl] -4- (2-methylphenylsulfonyl) piperidine, hydrochloride, mp 218-221 °; 1- [2- (2-fluorophenyl) ethyl] -4- (2-methylphenyl-sulfinyl) piperidine,
Hydrochlorid, F. 202-204°;Hydrochloride, mp 202-204 °;
1 -[2-(2,4-Difluorphenyl)-ethyl]-4-(2-methylphenyl-sulfonyl)-piperidin,1 - [2- (2,4-difluorophenyl) ethyl] -4- (2-methylphenylsulfonyl) piperidine,
Hydrochlorid, F. 235-240°; 1 -[2-(2,4-Difluorphenyl)-ethyl]-4-(2-methylphenyl-sulfinyl)-piperidin,Hydrochloride, mp 235-240 °; 1 - [2- (2,4-difluorophenyl) ethyl] -4- (2-methylphenylsulfinyl) piperidine,
Hydrochlorid, F. 216-217°;Hydrochloride, m.p. 216-217 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2,4-dimethylphenyl-sulfonyl)-piperidin,1- [2- (4-fluorophenyl) ethyl] -4- (2,4-dimethylphenyl-sulfonyl) -piperidine,
Hydrochlorid, F. 247-248°;Hydrochloride, mp 247-248 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2,4-dimethylphenyl-sulfinyl)-piperidin, Hydrochlorid, F. 237-238°;1- [2- (4-fluorophenyl) ethyl] -4- (2,4-dimethylphenylsulfinyl) piperidine, hydrochloride, mp 237-238 °;
1 -[2-(2-Fluorphenyl)-ethyl]-4-(2,4-dimethylphenyl-sulfonyl)-piperidin,1 - [2- (2-fluorophenyl) ethyl] -4- (2,4-dimethylphenylsulfonyl) piperidine,
Hydrochlorid, F. 242-244°;Hydrochloride, mp 242-244 °;
1-[2-(2-Fluorphenyl)-ethyl]-4-(2,4-dimethylphenyl-sulfinyl)-piperidin,1- [2- (2-fluorophenyl) ethyl] -4- (2,4-dimethylphenyl-sulfinyl) piperidine,
Hydrochlorid, F. 230-232°; 2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-sulfonyi}-phenol, Hydrochlorid, F.Hydrochloride, mp 230-232 °; 2- {1- [2- (4-fluorophenyl) ethyl] piperidine-4-sulfonyi} phenol, hydrochloride, F.
275°;275 °;
2-{1-[2-(4-Fluorphenyl)-ethyl]-piperidin-4-sulfinyl}-phenol, Hydrochlorid, F.2- {1- [2- (4-fluorophenyl) ethyl] piperidine-4-sulfinyl} phenol, hydrochloride, F.
262°;262 °;
4-{1 -[2-(4-Fluorphenyi)-ethyl]-piperidin-4-sulfonyl}-phenol, Hydrochlorid, F. 145°;4- {1 - [2- (4-fluorophenyi) ethyl] piperidine-4-sulfonyl} phenol, hydrochloride, mp 145 °;
4-{1 -[2-(4-Fluorphenyl)-ethyl]-piperidin-4-sulfinyl}-phenol, Hydrochlorid, F.4- {1 - [2- (4-fluorophenyl) ethyl] piperidine-4-sulfinyl} phenol, hydrochloride, F.
130-135°;130-135 °;
1-[2-(2,4-Difluorphenyl)-ethyl]-4-(2,4-dimethylphenyl-sulfonyl)-piperidin,1- [2- (2,4-difluorophenyl) ethyl] -4- (2,4-dimethylphenyl-sulfonyl) -piperidine,
Hydrochlorid, F. 255-257°; 1-[2-(2,4-Difluorphenyl)-ethyl]-4-(2,4-dimethylphenyl-sulfinyi)-piperidin,Hydrochloride, mp 255-257 °; 1- [2- (2,4-difluorophenyl) ethyl] -4- (2,4-dimethylphenyl-sulfinyi) -piperidine,
Hydrochlorid, F. 236-238°;Hydrochloride, mp 236-238 °;
1-[2-(4-Methoxyphenyl)-ethyl]-4-(2-methoxyphenyl-sulfonyl)-piperidin,1- [2- (4-methoxyphenyl) ethyl] -4- (2-methoxyphenyl-sulfonyl) -piperidine,
Hydrochlorid, F. 258-260°;Hydrochloride, mp 258-260 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2,4,6-trimethylphenyl-sulfonyl)-piperidin, Hydrochlorid, F. 280-283°;1- [2- (4-fluorophenyl) ethyl] -4- (2,4,6-trimethylphenylsulfonyl) piperidine, hydrochloride, mp 280-283 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2,4,6-trimethylphenyl-sulfinyl)-piperidin,1- [2- (4-fluorophenyl) -ethyl] -4- (2,4,6-trimethyl-phenyl-sulfinyl) piperidine,
Hydrochlorid, F. 220-223°;Hydrochloride, mp 220-223 °;
2-{1-[2-(2,4-Difluorphenyl)-ethyi]-piperidin-4-sulfonyl}-phenol, Hydrochlorid,2- {1- [2- (2,4-difluorophenyl) ethyl] piperidine-4-sulfonyl} phenol, hydrochloride,
F. >250°; 1-[2-(2,4-Difluorphenyl)-ethyl]-4-(2-methoxyphenyl-sulfonyl)-piperidin,F.> 250 °; 1- [2- (2,4-difluorophenyl) ethyl] -4- (2-methoxyphenyl-sulfonyl) -piperidine,
Hydrochlorid, F. 229-232°; 1 -[2-(2,4-Difluorphenyl)-ethyl -4-(2-methoxyphenyl-sulfinyl)-piperidin,Hydrochloride, mp 229-232 °; 1 - [2- (2,4-difluorophenyl) ethyl -4- (2-methoxyphenylsulfinyl) piperidine,
Hydrochlorid, F. 210-214°;Hydrochloride, mp 210-214 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- thiazol-2-sulfonyl)-piperidin, Hydrochlorid, F.1 - [2- (4-fluorophenyl) ethyl] -4-thiazole-2-sulfonyl) piperidine, hydrochloride, F.
197-198°; 1-[2-(4-Fluorphenyl)-ethyl]-4- thiazol-2-sulfinyl)-piperidin, Hydrochlorid, F.197-198 °; 1- [2- (4-fluorophenyl) ethyl] -4-thiazole-2-sulfinyl) piperidine, hydrochloride, F.
221-223°;221-223 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- thiophen-2-sulfonyl)-piperidin, Hydrochlorid,1 - [2- (4-fluorophenyl) ethyl] -4-thiophene-2-sulfonyl) piperidine, hydrochloride,
F. 239-241 °;Mp 239-241 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- thiophen-2-sulfinyl)-piperidin, Hydrochlorid, F. 206-207°;1 - [2- (4-fluorophenyl) ethyl] -4-thiophene-2-sulfinyl) piperidine, hydrochloride, mp 206-207 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- pyrimidin-2-sulfonyl)-piperidin, Hydrochlorid,1 - [2- (4-fluorophenyl) ethyl] -4-pyrimidine-2-sulfonyl) piperidine, hydrochloride,
F. 233-234°;M. 233-234 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- pyrimidin-2-sulfinyl)-piperidin, Hydrochlorid,1 - [2- (4-fluorophenyl) ethyl] -4-pyrimidine-2-sulfinyl) piperidine, hydrochloride,
F. 173-176°; 1 -[2-(4-Fluorphenyl)-ethyl]-4- 1 -methyl-1 H-imidazol-2-sulfonyl)-piperidin,Mp 173-176 °; 1 - [2- (4-fluorophenyl) ethyl] -4-1-methyl-1 H-imidazole-2-sulfonyl) piperidine,
Dihydrochlorid/Hydrat, F. 237 -239°;Dihydrochloride / hydrate, mp 237-239 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4 1 -methyl-1 H-imidazol-2-sulfinyl)-piperidin,1 - [2- (4-fluorophenyl) ethyl] -4 1 -methyl-1 H-imidazole-2-sulfinyl) piperidine,
Dihydrochlorid/Hydrat, F. 199 -202°;Dihydrochloride / hydrate, m.p. 199 -202 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- 2-chlorphenyl-sulfonyl)-piperidin, Hydrochlorid, F. 252-253°;1 - [2- (4-fluorophenyl) ethyl] -4- 2-chlorophenylsulfonyl) piperidine, hydrochloride, mp 252-253 °;
1 -[2-(4-Fluorphenyl)-ethyi]-4- 2-chlorphenyl-sulfinyl)-piperidin,1 - [2- (4-fluorophenyl) ethyl] -4- 2-chlorophenylsulfinyl) piperidine,
Hydrochlorid, F. 209-210°;Hydrochloride, mp 209-210 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4- 4-chiorphenyl-suifonyl)-piperidin,1 - [2- (4-fluorophenyl) ethyl] -4- 4-chlorophenyl-suifonyl) piperidine,
Hydrochlorid, F. 242-246°; 1 -[2-(4-Fluorphenyl)-ethyl]-4- 2-isopropylphenyl-sulfonyl)-piperidin,Hydrochloride, mp 242-246 °; 1 - [2- (4-fluorophenyl) ethyl] -4- 2-isopropylphenylsulfonyl) piperidine,
Hydrochlorid/Hydrat, F. 231-23 333°;Hydrochloride / hydrate, mp 231-23 333 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4 2-isopropylphenyl-sulfinyl)-piperidin,1 - [2- (4-fluorophenyl) ethyl] -4 2-isopropylphenylsulfinyl) piperidine,
Hydrochlorid, F. 200-203°;Hydrochloride, mp 200-203 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4 2-ethylphenyl-sulfonyl)-piperidin, Hydrochlorid, F. 229-231 °;1 - [2- (4-fluorophenyl) ethyl] -4 2-ethylphenylsulfonyl) piperidine, hydrochloride, mp 229-231 °;
1-[2-(4-Fluorphenyl)-ethyl]-4-(2-ethylphenyl-sulfinyl)-piperidin,1- [2- (4-fluorophenyl) ethyl] -4- (2-ethylphenyl-sulfinyl) piperidine,
Hydrochlorid/Hydrat, F. 204-206°;Hydrochloride / hydrate, mp 204-206 °;
1 -[2-(4-Fluorphenyl)-ethyl]-4-(1 -methyl-1 H-tetrazol-5-sulfinyl)-piperidin,1 - [2- (4-fluorophenyl) ethyl] -4- (1-methyl-1 H-tetrazole-5-sulfinyl) piperidine,
Hydrochlorid, F. 161-163°; 4-(2-Acetylphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, m.p. 161-163 °; 4- (2-acetylphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 224-226°; 4-(4-Acetylphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 224-226 °; 4- (4-acetylphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 242-244°;Hydrochloride, mp 242-244 °;
4-(4-Acetylphenyl-sulfιnyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (4-acetylphenyl sulfιnyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 225-227°; 4-(2-Ethoxycarbonylphenyl-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,Hydrochloride, mp 225-227 °; 4- (2-Ethoxycarbonylphenyl-sulfonyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 204-209°;Hydrochloride, mp 204-209 °;
4-(6-Chlor-pyridin-2-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin,4- (6-chloro-pyridin-2-sulfinyl) -1- [2- (4-fluorophenyl) -ethyl] -piperidine,
Hydrochlorid, F. 208°;Hydrochloride, mp 208 °;
4-(6-Chlor-pyridin-2-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid, F. 208°;4- (6-chloropyridine-2-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride, mp 208 °;
4-(1 H-lndol-3-sulfonyl)-1-[2-(2,4-difluorphenyl)-ethyl]-piperidin,4- (1 H-indole-3-sulfonyl) -1- [2- (2,4-difluorophenyl) ethyl] piperidine,
Hydrochlorid, (F. 150-200°);Hydrochloride, (mp 150-200 °);
4-(1 H-lndol-3-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,4- (1 H-indole-3-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride,
(F. 150-200°); 4-(3-Methyl-3H-imidazo[4,5-c]pyridin-4-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperidin, Dihydrochlorid, F. 227-229°;(F. 150-200 °); 4- (3-methyl-3H-imidazo [4,5-c] pyridine-4-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, dihydrochloride, mp 227-229 °;
4-(3-Methyl-3H-imidazo[4,5-c]pyridin-4-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]- piperidin, Dihydrochlorid, F. 173-175°;4- (3-methyl-3H-imidazo [4,5-c] pyridine-4-sulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, dihydrochloride, mp 173-175 °;
4-(1 H-Benzimidazol-2-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Dihydrochlorid, F. 110-125°;4- (1 H-benzimidazole-2-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, dihydrochloride, mp 110-125 °;
4-(1 -Methyl-1 H-imidazo[4,5-c]pyridin-4-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperidin, Dihydrochlorid/Hydrat, F. 186-192°;4- (1-Methyl-1 H-imidazo [4,5-c] pyridine-4-sulfonyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, dihydrochloride / hydrate, m.p. 186-192 °;
4-(1 -Methyl-1 H-imidazo[4,5-c]pyridin-4-sulfinyl)-1 -[2-(4-fluorphenyl)-ethyl]- piperidin, Dihydrochlorid/Dihydrat, F. 130-135°; 4-(2-Methyl-1 H-imidazo[4,5-c]pyridin-4-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]- piperidin, Dihydrochlorid/Dihydrat, F. 210-220°;4- (1-Methyl-1 H-imidazo [4,5-c] pyridine-4-sulfinyl) -1 - [2- (4-fluorophenyl) ethyl] piperidine, dihydrochloride / dihydrate, m.p. 130-135 °; 4- (2-methyl-1 H-imidazo [4,5-c] pyridine-4-sulfinyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, dihydrochloride / dihydrate, m.p. 210-220 °;
4-(lsochinolin-1-sulfonyl)-1-[2-(4-fluorphenyl)-ethyl]-piperidin, Hydrochlorid,4- (isoquinoline-1-sulfonyl) -1- [2- (4-fluorophenyl) ethyl] piperidine, hydrochloride,
F. 237-240°;F. 237-240 °;
4-(Chinolin-8-sulfonyl)-1-[2-(2,4-dichlorphenyl)-ethyl]-piperidin, Dihydrochlorid/Hydrat, F. 210-215°;4- (quinoline-8-sulfonyl) -1- [2- (2,4-dichlorophenyl) ethyl] piperidine, dihydrochloride / hydrate, mp 210-215 °;
4-(Chinolin-8-sulfinyl)-1-[2-(2,4-dichlorphenyl)-ethyl]-piperidin,4- (quinoline-8-sulfinyl) -1- [2- (2,4-dichlorophenyl) -ethyl] -piperidine,
Dihydrochlorid, F. 215-217°;Dihydrochloride, mp 215-217 °;
4-(Chinolin-8-sulfonyl)-1-[2-(naphthalin-2-yl)-ethyl]-piperidin, Hydrochlorid,4- (quinolin-8-sulfonyl) -1- [2- (naphthalin-2-yl) ethyl] piperidine, hydrochloride,
F. >280°; 4-(Chinolin-8-sulfinyl)-1 -[2-(naphthalin-2-yl)-ethyl]-piperidin, Hydrochlorid,F.> 280 °; 4- (quinolin-8-sulfinyl) -1 - [2- (naphthalin-2-yl) ethyl] piperidine, hydrochloride,
F. 205-213°; 4-(Chinolin-8-suifonyl)-1-[2-(2-chlor-4-fluorphenyl)-ethyl]-piperidin, Dihydrochlorid/Hydrat, F. 150-164°;F. 205-213 °; 4- (quinolin-8-suifonyl) -1- [2- (2-chloro-4-fluorophenyl) ethyl] piperidine, dihydrochloride / hydrate, mp 150-164 °;
4-(1 H-Benzimidazol-2-sulfonyl)-1-[2-(2-chlor-4-fluorphenyl)-ethyl]-piperidin, Dihydrochlorid. 4- (1 H-benzimidazole-2-sulfonyl) -1- [2- (2-chloro-4-fluorophenyl) ethyl] piperidine, dihydrochloride.
Die nachfolgenden Beispiele betreffen pharmazeutische Zubereitungen:The following examples relate to pharmaceutical preparations:
Beispiel A: InjektionsgläserExample A: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatriumhydrogenphosphat in 3 I zweifach destilliertem Wasser wird mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
Beispiel B: SuppositorienExample B: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Beispiel C: LösungExample C: solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9.38 g Na2HP04 x 2 H20, 28.48 g NaH2P04 x 12 H20 und 0.1 g Benzalkonium- chlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of Na 2 HP0 4 x 2 H 2 0, 28.48 g of NaH 2 P0 4 x 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel D: SalbeExample D: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel E: TablettenExample E: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1.2 kg Kartoffelstärke, 0.2 kg Talk und 0.1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
Beispiel F: DrageesExample F: coated tablets
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden. Beispiel G: KapselnAnalogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant. Example G: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel H: AmpullenExample H: ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird in Ampullen abgefüllt, unter aseptischen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is filled into ampoules, lyophilized under aseptic conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

Patentansprücheclaims
1. Verbindungen der Formel I1. Compounds of formula I.
Figure imgf000042_0001
worin
Figure imgf000042_0001
wherein
R1, R2 jeweils unabhängig voneinander einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oderR 1 , R 2 are each independently an unsubstituted or substituted by R 3 , R 4 and / or R 5 or
1010
Naphthylrest oder Het1,Naphthyl or Het 1 ,
R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, OH, CN, N02, NH2, NHA, NA2, NH-Acyl, Acyl, -SA, -SOA, S02A, COOA ^ oder Phenyl,R 3 , R 4 , R 5 each independently of one another shark, A, OA, OH, CN, N0 2 , NH 2 , NHA, NA 2 , NH-acyl, acyl, -SA, -SOA, S0 2 A, COOA ^ or phenyl,
X CH oder N,X CH or N,
Y S02 wenn X = N, oderY S0 2 if X = N, or
S, SO, S02 wenn X = CH, 20 Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch Hai,S, SO, S0 2 if X = CH, 20 Het 1 unsubstituted or one, two or three times by shark,
A, CN, CONH2, CH2COOA, Phenyl-S02, Acyl, OA oder OH substituiertes ungesättigtes heterocyclisches Ringsystem, welches eines, zwei oder drei gleiche oder verschiedene Heteroatome wie Stickstoff, Sauerstoff und SchwefelA, CN, CONH 2 , CH 2 COOA, phenyl-S0 2 , acyl, OA or OH substituted unsaturated heterocyclic ring system which has one, two or three identical or different heteroatoms such as nitrogen, oxygen and sulfur
25 enthält,25 contains
A Alkyl mit 1-6 C-Atomen, alk Alkylen mit 1-6 C-Atomen,A alkyl with 1-6 C atoms, alk alkylene with 1-6 C atoms,
Hai F, Cl, Br oder I,Shark F, Cl, Br or I,
30 bedeuten, wobei Het1 ≠2,1 ,3-Benzoxadiazol- oder 2,1 , 3-Benzothiadiazol-yl, sowie deren physiologisch unbedenklichen Salze und Solvate.30 mean, where Het 1 ≠ 2,1, 3-benzoxadiazol- or 2,1, 3-benzothiadiazol-yl, and their physiologically acceptable salts and solvates.
2. Verbindungen gemäß Anspruch 12. Compounds according to claim 1
35 a) 8-{4-[2-(4-Fluorphenyl)-ethyl]-piperazin-1-sulfonyl}-chinolin; b) 4-(4-Fluorphenyl-sulfonyl)-1 -[2-(4-fluorphenyl)-ethyl]-pιperιdιn, c) 2-Chlor-6-{1 -[2-(4-fluorphenyl)-ethyl]-pιperιdιn-4-sulfonyi}- pyπdin, d) 4-(2-Methoxyphenyl-sulfanyl)-1 -[2-(4-fluorphenyl)-ethyl]- pipeπdin, e) 4-(4-Methylphenyl-sulfinyl)-1-[2-(4-fluorphenyl)-ethyl]-pιperιdιn, f) 4-(3-Cyan-1 H-ιndol-5-sulfonyl)-1 -[2-(4-fluorphenyl)-ethylj- piperazin35 a) 8- {4- [2- (4-fluorophenyl) ethyl] piperazin-1-sulfonyl} quinoline; b) 4- (4-fluorophenylsulfonyl) -1 - [2- (4-fluorophenyl) ethyl] -pιperιdιn, c) 2-chloro-6- {1 - [2- (4-fluorophenyl) ethyl] -pιperιdιn-4-sulfonyi} - pyπdin, d) 4- (2-methoxyphenyl-sulfanyl) -1 - [2- (4-fluorophenyl) -ethyl] - pipeπdin, e) 4- (4-methylphenyl-sulfinyl) - 1- [2- (4-fluorophenyl) ethyl] -pιperιdιn, f) 4- (3-cyano-1 H-indol-5-sulfonyl) -1 - [2- (4-fluorophenyl) ethylj-piperazine
sowie deren physiologisch unbedenklichen Salze und Soivate.and their physiologically acceptable salts and derivatives.
Verfahren zur Herstellung von Verbindungen der Formel I gemäß Anspruch 1 , worin X N bedeutet, dadurch gekennzeichnet, daß manA process for the preparation of compounds of formula I according to claim 1, wherein X is N, characterized in that
a) eine Verbindung der Formel IIa) a compound of formula II
R1-al — N NHR 1 -al - N NH
\ /\ /
worin R1 und alk die in Anspruch 1 angegebenen Bedeutungen haben, mit einer Verbindung der Formel IIIwherein R 1 and alk have the meanings given in claim 1, with a compound of formula III
R -Y-LR -Y-L
worin L Cl, Br, I oder eine freie oder reaktionsfähig funktionell abgewandelte OH-Gruppe bedeutet, und R2 und Y die in Anspruch 1 angegebenen Bedeutungen habenwherein L is Cl, Br, I or a free or reactively functionally modified OH group, and R 2 and Y have the meanings given in claim 1
umsetzt,implements,
oder b) gegebenenfalls einen der Reste R und/oder R2 in einen anderen Rest R1 und/oder R2 umwandelt, indem man beispielsweise eine OA-Gruppe unter Bildung einer OH-Gruppe spaltet und/oder eine CHO-Gruppe in eine CN-Gruppe umwandeltor b) optionally converting one of the radicals R and / or R 2 into another radical R 1 and / or R 2 , for example by cleaving an OA group to form an OH group and / or converting a CHO group into a CN Group converts
und/oder eine erhaltene Base der Formel I durch Behandein mit einer Säure in eines ihrer Salze umwandelt.and / or a base of the formula I obtained is converted into one of its salts by treatment with an acid.
Verfahren zur Herstellung von Verbindungen der Formel I gemäßProcess for the preparation of compounds of formula I according to
Anspruch 1 , worin X CH bedeutet, dadurch gekennzeichnet, daß manClaim 1, wherein X is CH, characterized in that
a) eine Verbindung der Formel IVa) a compound of formula IV
Figure imgf000044_0001
Figure imgf000044_0001
worin R2 die in Anspruch 1 angegebene Bedeutung hat, mit einer Verbindung der Formel Vwherein R 2 has the meaning given in claim 1, with a compound of formula V.
R1-alk-L VR 1 -alk-L V
worin L Cl, Br, I oder eine freie oder reaktionsfähig funktioneil abgewandelte OH-Gruppe bedeutet, und R und alk die in Anspruch 1 angegebenen Bedeutungen haben,in which L is Cl, Br, I or a free or reactively modified OH group, and R and alk have the meanings given in Claim 1,
umsetzt,implements,
und anschließend oxidiert,and then oxidized,
oderor
b) gegebenenfalls einen der Reste R1 und/oder R2 in einen anderen Rest R1 und/oder R2 umwandelt, indem man beispielsweise eine OA-Gruppe unter Bildung einer OH-Gruppe spaltet und/oder eine CHO-Gruppe in eine CN-Gruppe umwandeltb) optionally converting one of the radicals R 1 and / or R 2 into another radical R 1 and / or R 2 , for example by cleaves an OA group to form an OH group and / or converts a CHO group into a CN group
und/oder eine erhaltene Base der Formel I durch Behandeln mit einer Säure in eines ihrer Salze umwandelt.and / or converts a base of the formula I obtained into one of its salts by treatment with an acid.
Verbindungen der Formel I gemäß Anspruch 1 , sowie ihrer physiologisch unbedenklichen Salze und Solvate als Arzneimittel.Compounds of formula I according to claim 1, and their physiologically acceptable salts and solvates as medicaments.
6. Verbindungen der Formel I6. Compounds of formula I.
Figure imgf000045_0001
worin
Figure imgf000045_0001
wherein
R1, R2 jeweils unabhängig voneinander einen unsubstituierten oder durch R3, R4 und/oder R5 substituierten Phenyl- oderR 1 , R 2 are each independently an unsubstituted or substituted by R 3 , R 4 and / or R 5 or
Naphthylrest oder Het1,Naphthyl or Het 1 ,
R3, R4, R5 jeweils unabhängig voneinander Hai, A, OA, OH, CN, N02,R 3 , R 4 , R 5 each independently of one another shark, A, OA, OH, CN, N0 2 ,
NH2, NHA, NA2, NH-Acyl, Acyl, -SA, -SOA, S02A, COOA oder Phenyl, X CH oder N,NH 2 , NHA, NA 2 , NH-acyl, acyl, -SA, -SOA, S0 2 A, COOA or phenyl, X CH or N,
Y S02 wenn X = N, oderY S0 2 if X = N, or
S, SO, S02 wenn X = CH, Het1 unsubstituiertes oder ein-, zwei- oder dreifach durch Hai,S, SO, S0 2 if X = CH, Het 1 unsubstituted or one, two or three times by shark,
A, CN, CONH2, CH2COOA, Phenyl-S02, Acyl, OA oder OH substituiertes ungesättigtes heterocyclisches Ringsystem, welches eines, zwei oder drei gleiche oder verschiedeneA, CN, CONH 2 , CH 2 COOA, phenyl-S0 2 , acyl, OA or OH substituted unsaturated heterocyclic ring system, which one, two or three identical or different
Heteroatome wie Stickstoff, Sauerstoff und Schwefel enthält, A Alkyl mit 1-6 C-Atomen, alk Alkylen mit 1-6 C-Atomen, Hai F, Cl, Br oder I, bedeuten, sowie ihrer physiologisch unbedenklichen Salze und Solvate alsContains heteroatoms such as nitrogen, oxygen and sulfur, A alkyl with 1-6 C atoms, alk alkylene with 1-6 C atoms, Shark F, Cl, Br or I, as well as their physiologically acceptable salts and solvates as
Arzneimittel mit 5-HT2A-Rezeptor-antagonistischer Wirkung.Medicinal products with 5-HT 2A receptor antagonistic effect.
7. Arzneimittel nach Anspruch 5 oder 6 zur Behandlung von Psychosen, Schizophrenie, Depression, neurologischen Störungen, Gedächtnisstörungen, Morbus Parkinson, amyotropher Lateralsklerose, der Alzheimer Krankheit, der Huntington Krankheit, Essstörungen wie Buiimie, nervöser Anorexie, des prämenstrualen7. Medicament according to claim 5 or 6 for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, eating disorders such as Buiimie, nervous anorexia, premenstrual
Syndroms und/oder zur positiven Beeinflussung von Zwangsverhalten (obsessive-compulsive disorder, OCD).Syndrome and / or to positively influence obsessive behavior (obsessive-compulsive disorder, OCD).
8. Pharmazeutische Zubereitung, enthaltend mindestens ein Arznei- mittel gemäß Anspruch 5 oder 6, sowie gegebenenfalls Trägerund/oder Hilfsstoffe und gegebenenfalls andere Wirkstoffe.8. Pharmaceutical preparation containing at least one medicament according to claim 5 or 6, and optionally carriers and / or auxiliaries and optionally other active substances.
9. Verwendung von Verbindungen gemäß Anspruch 1 und/oder von deren physiologisch unbedenklichen Salzen und Solvaten zur Herstellung eines Arzneimittels mit 5-HT2A-Rezeptor-antagonistischer9. Use of compounds according to claim 1 and / or of their physiologically acceptable salts and solvates for the manufacture of a medicament with 5-HT 2A receptor-antagonistic
Wirkung.Effect.
10. Verwendung nach Anspruch 9 zur Herstellung eines Arzneimittels zur Behandlung von Psychosen, Schizophrenie, Depression, neurologischen Störungen, Gedächtnisstörungen, Morbus Parkinson, amyotropher Lateralsklerose, der Alzheimer Krankheit, der10. Use according to claim 9 for the manufacture of a medicament for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease
Huntington Krankheit, Essstörungen wie Buiimie, nervöser Anorexie, des prämenstrualen Syndroms und/oder zur positiven Beeinflussung von Zwangsverhalten (obsessive-compulsive disorder, OCD). Huntington's disease, eating disorders such as buiimia, nervous anorexia, premenstrual syndrome and / or to positively influence compulsive behavior (obsessive-compulsive disorder, OCD).
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